4,4-disubstituted-3,4-dihydro-2(1H)-quinazolinones useful as HIV reverse transcriptase inhibitors

ABSTRACT

The present invention relates to 4,4-disubstituted-3,4-dihydro-2(1H)-quinazolinones of formula I:                    
     or stereoisomeric forms, stereoisomeric mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of HIV reverse transcriptase, and to pharmaceutical compositions and diagnostic kits comprising the same, and methods of using the same for treating viral infection or as an assay standard or reagent.

This is a divisional of application Ser. No. 09/056,820, filed Apr. 8, 1998, now U.S. Pat. No. 6,124,302, which claims the benefit of Provisional Application No. 60/043,115, filed Apr. 9, 1997 and 60/071,322, filed Jan. 14, 1998.

FIELD OF THE INVENTION

This invention relates generally to 4,4-disubstituted-3,4-dihydro-2(1H)-quinazolinones which are useful as inhibitors of HIV reverse transcriptase, pharmaceutical compositions and diagnostic kits comprising the same, methods of using the same for treating viral infection or as assay standards or reagents, and intermediates and processes for making the same.

BACKGROUND OF THE INVENTION

Two distinct retroviruses, human immunodeficiency virus (HIV) type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to the immunosuppressive disease, acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which predisposes them to debilitating and ultimately fatal opportunistic infections.

The disease AIDS is the end result of an HIV-1 or HIV-2 virus following its own complex life cycle. The virion life cycle begins with the virion attaching itself to the host human T-4 lymphocyte immune cell through the bonding of a glycoprotein on the surface of the virion's protective coat with the CD4 glycoprotein on the lymphocyte cell. Once attached, the virion sheds its glycoprotein coat, penetrates into the membrane of the host cell, and uncoats its RNA. The virion enzyme, reverse transcriptase, directs the process of transcribing the RNAinto single-stranded DNA. The viral RNA is degraded and a second DNA strand is created. The now double-stranded DNA is integrated into the human cell's genes and those genes are used for virus reproduction.

At this point, RNA polymerase transcribes the integrated DNA into viral RNA. The viral RNA is translated into the precursor gag-pol fusion polyprotein. The polyprotein is then cleaved by the HIV protease enzyme to yield the mature viral proteins. Thus, HIV protease is responsible for regulating a cascade of cleavage events that lead to the virus particle's maturing into a virus that is capable of full infectivity.

The typical human immune system response, killing the invading virion, is taxed because the virus infects and kills the immune system's T cells. In addition, viral reverse transcriptase, the enzyme used in making a new virion particle, is not very specific, and causes transcription mistakes that result in continually changed glycoproteins on the surface of the viral protective coat. This lack of specificity decreases the immune system's effectiveness because antibodies specifically produced against one glycoprotein may be useless against. another, hence reducing the number of antibodies available to fight the virus. The virus continues to reproduce while the immune response system continues to weaken. Eventually, the HIV largely holds free reign over the body's immune system, allowing opportunistic infections to set in and without the administration of antiviral agents, immunomodulators, or both, death may result.

There are at least three critical points in the virus's life cycle which have been identified as possible targets for antiviral drugs: (1) the initial attachment of the virion to the T-4 lymphocyte or macrophage site, (2) the transcription of viral RNA to viral DNA (reverse transcriptase, RT), and (3) the processing of gag-pol protein by HIV protease.

Inhibition of the virus at the second critical point, the viral RNA to viral DNA transcription process, has provided a number of the current therapies used in treading AIDS. This transcription must occur for the virion to reproduce because the virion's genes are encoded in RNA and the host cell reads only DNA. By introducing drugs that block the reverse transcriptase from completing the formation of viral DNA, HIV-1 replication can be stopped.

A number of compounds that interfere with viral replication have been developed to treat AIDS. For example, nucleoside analogs, such as 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxycytidine (ddC), 2′,3′-dideoxythymidinene (d4T), 2′,3′-dideoxyinosine (ddI), and 2′,3′-dideoxy-3′-thia-cytidine (3TC) have been shown to be relatively effective in halting HIV replication at the reverse transcriptase (RT) stage.

An active area of research is in the discovery of non-nucleoside HIV reverse transcriptase inhibitors. As an example, it has been found that certain benzoxazinones and quinazolinones are active in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS.

U.S. Pat. No. 5,519,021 describe reverse transcriptase inhibitors which are benzoxazinones of the formula:

wherein X is a halogen, Z may be O.

EP 0,530,994 and WO 93/04047 describe HIV reverse transcriptase inhibitors which are quinazolinones of the formula A:

wherein G is a variety of groups, R³ and R⁴ may be H, Z may be O, R² may be unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycle, and optionally substituted aryl, and R¹ may be a variety of groups including substituted alkyl.

WO 95/12583 also describes HIV reverse transcriptase inhibitors of formula A. In this publication, G is a variety of groups, R³ and R⁴ may be H, Z may be O, R² is substituted alkenyl or substituted alkynyl, and R¹ is cycloalkyl, alkynyl, alkenyl, or cyano. WO 95/13273 illustrates the asymmetric synthesis of one of the compounds of WO 95/12583, (S)-(−)-6-chloro-4-cyclopropyl-3,4-dihydro-4((2-pyridy)ethynyl)-2(1H)-quinazolinone.

Synthetic procedures for making quinazolinones like those described above are detailed in the following references: Houpis et al, Tetr. Lett. 1994, 35(37), 6811-6814; Tucker et al, J. Med. Chem. 1994, 37, 2437-2444; and, Huffman et al, J. Org. Chem. 1995, 60, 1590-1594.

DE 4,320,347 illustrates quinazolinones of the formula:

wherein R is a phenyl, carbocyclic ring, or a heterocyclic ring. Compounds of this sort are not considered to be part of the present invention.

Even with the current success of reverse transcriptase inhibitors, it has been found that HIV patients can become resistant to a single inhibitor. Thus, it is desirable to develop additional inhibitors to further combat HIV infection.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novel reverse transcriptase inhibitors.

It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.

It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need thereof a therapeutically effective combination of (a) one of the compounds of the present invention and (b) one or more compounds selected form the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

It is another object of the present invention to provide pharmaceutical compositions with reverse transcriptase inhibiting activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.

It is another object of the present invention to provide a method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of the present invention.

It is another object of the present invention to provide a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I):

wherein R¹, R², R³, and R⁸ are defined below, stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, are effective reverse transcriptase inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] Thus, in a first embodiment, the present invention provides a novel compound of formula I:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

R¹ is C₁₋₃ alkyl substituted with 1-7 halogen;

R² is selected from C₁₋₅ alkyl substituted with 1-2 R⁴, C₂₋₅ alkenyl substituted with 1-2 R⁴, and C₂₋₅ alkynyl substituted with 1 R⁴;

R³, at each occurrence, is independently selected from C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, F, Cl, Br, I, NR⁵R^(5a), NO₂, CN, C(O)R⁶, NHC(O)R⁷, and NHC(O)NR⁵R^(5a);

alternatively, if two R³'s are present and are attached to adjacent carbons, then they may combine to form —OCH₂O—;

R⁴ is selected from C₃₋₅ cycloalkyl substituted with 0-2 R³, phenyl substituted with 0-5 R³, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-2 R³;

R⁵ and R^(5a) are independently selected from H and C₁₋₃ alkyl;

R⁶ is selected from H, OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, and NR⁵R^(5a);

R⁷ is selected from C₁₋₃ alkyl and C₁₋₃ alkoxy;

R⁸ is selected from H, C₃₋₅ cycloalkyl, and C₁₋₃ alkyl; and,

n is selected from 0, 1, 2, 3, and 4.

[2] In a preferred embodiment, the present invention provides a novel compound of formula I, wherein:

R¹ is C₁₋₃ alkyl substituted with 1-7 halogen;

R² is selected from C₁₋₅ alkyl substituted with 1 R⁴, C₂₋₅ alkenyl substituted with 1 R⁴, and C₂₋₅ alkynyl substituted with 1 R⁴;

R³, at each occurrence, is independently selected from C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, F, Cl, Br, I, NR⁵R^(5a), NO₂, CN, C(O)R⁶, NHC(O)R⁷, and NHC(O)NR⁵R^(5a);

alternatively, if two R³'s are present and are attached to adjacent carbons, then they may combine to form —OCH₂O—;

R⁴ is selected from C₃₋₅ cycloalkyl substituted with 0-2 R³, phenyl substituted with 0-2 R³, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 R³;

R⁵ and R^(5a) are independently selected from H, CH₃ and C₂H₅;

R⁶ is selected from H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, and NR⁵R^(5a);

R⁷ is selected from CH₃, C₂H₅, OCH₃, and OC₂H₅;

R⁸ is selected from H, cyclopropyl, CH₃ and C₂H₅; and,

n is selected from 0, 1, 2, and 3.

[3] In a more preferred embodiment, the present invention provides a novel compound of formula I, wherein:

R¹ is selected from CF₃, and C₂F₅;

R² is selected from C₁₋₃ alkyl substituted with 1 R⁴, C₂₋₃ alkenyl substituted with 1 R⁴, and C₂₋₃ alkynyl substituted with 1 R⁴;

R³, at each occurrence, is independently selected from C₁₋₃ alkyl, OH, C₁₋₃ alkoxy, F, Cl, Br, I, NR⁵R^(5a), NO₂, CN, C(O)R⁶, NHC(O)R⁷, and NHC(O)NR⁵R^(5a);

alternatively, if two R³'s are present and are attached to adjacent carbons, then they may combine to form —OCH₂O—;

R⁴ is selected from C₃₋₅ cycloalkyl substituted with 0-2 R³, phenyl substituted with 0-2 R³, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 R³;

R⁵ and R^(5a) are independently selected from H, CH₃ and C₂H₅;

R⁶ is selected from H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, and NR⁵R^(5a);

R⁷ is selected from CH₃, C₂H₅, OCH₃, and OC₂H₅;

R⁸ is selected from H, CH₃ and C₂H₅; and,

n is selected from 0, 1, and 2.

[4] In an even more preferred embodiment, the present invention provides a novel compound of formula I, wherein:

R¹ is CF₃;

R² is selected from C₁₋₃ alkyl substituted with 1 R⁴, C₂₋₃ alkenyl substituted with 1 R⁴, and C₂₋₃ alkynyl substituted with 1 R⁴;

R³, at each occurrence, is independently selected from C₁₋₃ alkyl, OH, C₁₋₃ alkoxy, F, Cl, NR⁵R^(5a), NO₂, CN, C(O)R⁶, NHC(O)R⁷, and NHC(O)NR⁵R^(5a);

alternatively, if two R³'s are present and are attached to adjacent carbons, then they may combine to form —OCH₂O—;

R⁴ is selected from cyclopropyl substituted with 0-1 R³, phenyl substituted with 0-2 R³, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 R³, wherein the heterocyclic system is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, and 2-imidazolyl;

R⁵ and R^(5a) are independently selected from H, CH₃ and C₂H₅;

R⁶ is selected from H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, and NR⁵R^(5a);

R⁷ is selected from CH₃, C₂H₅, OCH₃, and OC₂H₅;

R⁸ is selected from H, CH₃ and C₂H₅; and,

n is selected from 1 and 2.

[5] In a further preferred embodiment, wherein the compound is of formula Ia

[5] In a further preferred embodiment, wherein the compound is of formula Ib:

[7] In a further preferred embodiment, the compound of formula I is selected from:

(+/−)-6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+/−)-6-Chloro-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+/−)-6-Chloro-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+/−)-4-Cyclopropylethynyl-6-methoxy-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+/−)-6-Methoxy-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+/−)-6-Methoxy-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+/−)-4-Cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+/−)-5,6-Difluoro-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+/−)-5,6-Difluoro-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+/−)-4-Cyclopropylethynyl-6-fluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+/−)-6-Fluoro-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+/−)-6-Fluoro-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+/−)-6-Fluoro-4-(2′-2-pyridyl)ethyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+/−)-6-Fluoro-4-phenylethyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(−)-6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+)-6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+)-4-Cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(−)-4-Cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+)-4-E-Cyclopropylethenyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; and,

(−)-6-Chloro-4-E-cyclopropylethenyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

or a pharmaceutically acceptah salt thereof.

[8] In a second embodiment, the present invention provides a novel compound of formula II:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

R² is C≡C—R^(4a);

R³ is selected from C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, F, Cl, Br, I, NR⁵R^(5a), NO₂, CN, C(O)R⁶, NHC(O)R⁷, and NHC(O)NR⁵R^(5a);

R⁴a is selected from methyl, ethyl, n-propyl, i-propyl, i-butyl, t-butyl, and i-pentyl;

R⁵ and R^(5a) are independently selected from H and C₁₋₃ alkyl;

R⁶ is selected from H, OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, and NR⁵R^(5a);

R⁷ is selected from C₁₋₃ alkyl and C₁₋₃ alkoxy;

R⁸ is selected from H, C₃₋₅ cycloalkyl, and C₁₋₃ alkyl; and,

n is selected from 0, 1, 2, 3, and 4.

[9] In another preferred embodiment, the present invention provides a novel compound of formula II, wherein:

R² is C≡C—R^(4a);

R³ is selected from C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, F, Cl, Br, I, NR⁵R^(5a), NO₂, CN, C(O)R⁶, and NHC(O)R⁷;

R^(4a) is selected from methyl, ethyl, n-propyl, i-propyl, i-butyl, t-butyl, and i-pentyl;

R⁵ and R^(5a) are independently selected from H, CH₃ and C₂H₅;

R⁶ is selected from H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, and NR⁵R^(5a);

R⁷ is selected from CH₃, C₂H₅, OCH₃, and OC₂H₅;

R⁸ is selected from H, cyclopropyl, CH₃ and C₂H₅; and,

n is selected from 0, 1, and 2.

[10] In a further preferred embodiment, wherein the compound is of formula IIa

[11] In a further preferred embodiment, wherein the compound is of formula Ilb:

[12] In another more preferred embodiment, the compound of formula II is selected from:

(+/−)-6-Chloro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+/−)-6-Chloro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+/−)-4-Isopropylethynyl-6-methoxy-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+/−)-5,6-Difluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+/−)-5,6-Difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+/−)-5,6-Difluoro-4-isopentyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+/−)-6-Fluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+/−)-6-Fluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(−)-5,6-Difluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(+)-5,6-Difluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

(−)-5,6-Difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; and,

(+)-5,6-Difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;

or a pharmaceutically acceptable salt thereof.

In a third embodiment, the present invention provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or II or pharmaceutically acceptable salt form thereof.

In a fourth embodiment, the present invention provides a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of formula I or II or pharmaceutically acceptable salt form thereof.

In a fifth embodiment, the present invention provides a novel method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of:

(a) a compound of formula I or II; and,

(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

In another preferred embodiment, the reverse transcriptase inhibitor is selected from AZT, 3TC, ddI, ddC, d4T, delavirdine, TIBO derivatives, BI-RG-587, nevirapine, L-697,661, LY 73497, Ro 18,893, loviride, trovirdine, MKC-442, and HBY 097, and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478, nelfinavir, KNI-272, CGP-61755, U-140690, and ABT-378.

In an even more preferred embodiment, the reverse transcriptase inhibitor is selected from AZT and 3TC and the protease inhibitor is selected from saquinavir, ritonavir, nelfinavir, and indinavir.

In a still further preferred ebodiment, the reverse transcriptase inhibitor is AZT.

In another still further preferred embodiment, the rotease inhibitor is indinavir.

In a sixth embodiment, the present invention provides a pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of:

(a) a compound of formula I or II; and,

(b) at least one compound selected, from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, in one or more sterile containers.

In a seventh embodiment, the present invention provides a novel method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of formula I or II.

In a eighth embodiment, the present invention to provides a novel a kit or container comprising a compound of formula I or II in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.

DEFINITIONS

As used herein, the following terms and expressions have the indicated meanings. It will be appreciated that the compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.

The processes of the present invention are contemplated to be practiced on at least a multigram scale, kilogram scale, multikilogram scale, or industrial scale. Multigram scale, as used herein, is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more. Multikilogram scale, as used herein, is intended to mean the scale wherein more than one kilogram of at least one starting material is used. Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.

As used herein, “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl; t-butyl, n-pentyl, and s-pentyl. “Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentaf luoroethyl, and pentachloroethyl; “Alkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. “Cycloalkyl” is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. Alkenyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like. “Alkynyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo and iodo. “Counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.

As used herein, “aryl” or “aromatic residue” is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as phenyl or naphthyl. As used herein, “carbocycle” or “carbocyclic residue” is intended to mean any stable 3- to 5-membered monocyclic ring, which may be saturated or partially unsaturated. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” or “heterocyclic system” is intended to mean a stable 5- to 6-membered monocyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term “aromatic heterocyclic system” is intended to mean a stable 5- to 6-membered monocyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 3 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, 2-pyrrolidonyl, 2H-pyrrolyl, 4-piperidonyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, and oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

As used herein, “HIV reverse transcriptase inhibitor” is intended to refer to both nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT). Examples of nucleoside RT inhibitors include, but are not limited to, AZT, ddC, ddI, d4T, and 3TC. Examples of non-nucleoside RT inhibitors include, but are no limited to, delavirdine (Pharmacia and Upjohn U90152S), TIBO derivatives, BI-RG-587, nevirapine (Boehringer Ingelheim), L-697,661, LY 73497, Ro 18,893 (Roche), loviride (Janssen), trovirdine (Lilly), MKC-442 (Triangle), and HBY 097 (Hoechst).

As used herein, “HIV protease inhibitor” is intended to refer to compounds which inhibit HIV protease. Examples include, but are not limited, saquinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538), indinavir (Merck, MK-639), VX-478 (Vertex/Glaxo Wellcome), nelfinavir (Agouron, AG-1343), KNI-272 (Japan Energy), CGP-61755 (Ciba-Geigy), U-140690 (Pharmacia and Upjohn), and ABT-378. Additional examples include the cyclic protease inhibitors disclosed in WO93/07128, WO 94/19329, WO 94/22840, and PCT Application Number US96/03426.

As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxyymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of.which is hereby incorporated by reference.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

“Prodrugs” are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) or other formulas or compounds of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the present invention, for example formula (I), are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein the hydroxy or amino group is bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl or free amino, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention, and the like.

“Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contemplated by the present invention.

“Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O) group, then 2 hydrogens on the atom are replaced.

“Therapeutically effective amount” is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.

SYNTHESIS

The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Each of the references cited below are hereby incorporated herein by reference.

Scheme 1 illustrates a method of preparing keto-anilines from an appropriately substituted 2-aminobenzoic acid. The acid is converted to its N-methoxy-N-methyl amide derivative which can then be displaced to obtain the R¹-substituted ketone. The keto-anilines are useful intermediates for the presently claimed compounds.

Scheme 2 describes another method of preparing keto-anilines, this time from an appropriately substituted aniline. After iodination and amine protection, a group such as trifluoromethyl can be introduced using a strong base and ethyl trifluoroacetate. Deprotection provides the keto-aniline. Additional means of preparing keto-anilines are known to one of skill in the art, e.g, Houpis et al, Tetr. Lett. 1994, 35(37), 6811-6814, the contents of which are hereby incorporated herein by reference.

Another method of making ₂-trifluoroacetylanilines is shown in Scheme 3. After forming the protected aniline, the amide is then reduced and the trifluoromethyl group added. Oxidation with an oxidant, such as MnO₂, provides the useful intermediate.

Using the general method detailed in Scheme 4, one can prepare compounds of the present invention. Keto-aniline 1, which may be prepared by the methods desribed in Schemes 1 and 2, is treated with trimethylsilyl isocyanate in dry tetrahydofuran in the presence of dimethylaminopyridine followed by tetrabutylammonium fluoride to give the hydroxy-urea 2. The hydroxy-urea 2 is then dehydrated with a dehydrating agent such as 4 Å molecular sieves in refluxing toluene or xylenes to give the ketimine 3. A substituted acetylenic R² group is added by treating the ketimine 3 with a lithium acetylide, which is prepared in a separate vessel by reacting the corresponding substituted acetylene with n-butyllithium in dry tetrahydrofuran, to give the 4,4-disubstituted 3,4-dihydro-2(1H)-quinazolinone 4, a compound of formula I. The acetylenic bond of the compound 4 may be reduced, e.g., by catalytic hydrogenation, to give the corresponding alkenyl group (not shown) or the saturated compound 5.

Other R² groups may also be introduced by directly reacting the imine 3 with a lithiate R²Li or a Grignard reagent R²MgX in the presence or absence of Lewis acid catalyst, such as BF₃ etherate. See also Huffman et al, J. Org. Chem. 1995, 60, 1590-1594, the contents of which are hereby incorporated herein by reference.

In certain instances, one enantiomer of a compound of Formula I or II may display superior activity compared with the other. When required, separation of the racemic material can be achieved by HPLC using a chiral column as exemplified in Examples 27-34 (Scheme 4) or by a resolution using a resolving agent such as camphonic chloride as in Thomas J. Tucker, et al, J. Med. Chem. 1994, 37, 2437-2444. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g. Mark A. Huffman, et al, J. Org. Chem. 1995, 60, 1590-1594.

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

Abbreviations used in the Examples are defined as follows: “° C.” for degrees Celsius, “d” for doublet, “dd” for doublet of doublets, “eq” for equivalent or equivalents, “g” for gram or grams, “mg” for milligram or milligrams, “mL” for milliliter or milliliters, “H” for hydrogen or hydrogens, “hr” for hour or hours, “m” for multiplet, “M” for molar, “min” for minute or minutes, “MHz” for megahertz, “MS” for mass spectroscopy, “nmr” or “NMR” for nuclear magnetic resonance spectroscopy, “t” for triplet, “TLC” for thin layer chromatography, “EDAC” for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, “DIPEA” for diisopropylethylamine, “TBAF” for tetrabutylammonium fluoride, “LAH” for lithium aluminium hydride, and “TEA” for triethylamine.

Example 1 Prepration of (+/−)-6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=Cyclopropyl)

Step 1. Synthesis of II-a from I-a.

To a solution of compound I-a (4.55 g, 20.2 mmol) in anhydrous THF (40 mL) was added dimethylaminopyridine (0.25 g, 2.02 mmol) and trimethylsilyl isocyanate (6.05 g, 7.11 mL, 52.5 mmol). The mixture was stirred at room temperature for approximately 16 hours, then tetrabutylammonium fluoride (21 mL of 1 M solution in THF) was added. The thick slurry was diluted with additional THF (20 mL) and stirred at room temperature for 0.5 hours. The THF was removed under reduced pressure, the residue was taken up in EtOAc (100 mL) and washed sequentially with 1 N HCl (70 mL), saturated aqueous NaHCO₃ (70 mL) and saturated aqueous NaCl (50 mL). The organic phase was dried over MgSO₄, filtered and concentrated under reduced pressure to afford a light yellow solid. The. yellow color was removed upon trituration with hexanes to afford IIa (5.09 g, 94%) as a white solid: ¹H NMR (300 MHz, acetone-d₆) δ 9.06 (br s, 1H), 7.48 (s, 1H), 7.40 (br s, 1H), 7.34 (dd, J=8.8, 2.6 Hz, 1H), 6.97 (d, J=8.8 Hz, 1H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −86.33, −86.35; IR (KBr Pellet) 1724, 1678, 1398, 1198, 1174 cm⁻¹; MS (CI) m/e 266 (MH⁺, 100).

Step 2. Synthesis of III-a from II-a.

A suspension of II-a (5.09 g, 19.1 mmol) in toluene (150 mL) containing 4 Å molecular sieves (approximately 100 mg) was heated at reflux for 16 hours. The resulting clear yellow solution was cooled to room temperature, the precipitated solids were dissolved in acetone and the molecular sieves were removed by vacuum filtration. The filtrate was concentrated under reduced pressure, and triturated with hexanes to afford III-a (4.25 g, 89%) as a yellow solid: ¹H NMR (300 MHz, acetone-d₆) δ 7.86-7.82 (m, 2H), 7.61 (d, J=8.8 Hz, 1H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −67.88.

Step 3. Synthesis of IV-a from IlIa.

A solution of cyclopropylacetylene (13.0 mL of 30 wt % solution in toluene/THF/hexanes, 59.0 mmol) in anhydrous THF (118 mL) was cooled to −78° C., treated with n-BuLi (32.8 mL of 1.6 M solution in hexanes, 52.4 mmol), warmed to 0° C. in an ice bath, and aged for 0.5 h. To a solution of III-a (3.12 g, 12.6 mmol) in anhydrous THF (66 mL) at −78 C. was added the lithium acetylide over approximately 10 minutes. To this was added boron trifluoride etherate (0.89 g, 0.80 mL, 6.28 mmol), followed by removal of the cooling bath. The reaction was allowed to reach room temperature and stirred at room temperature for 4 hours before quenching with 1 M citric acid (100 mL). The mixture was concentrated under reduced pressure to ½ original volume, diluted with EtOAc (200 mL), the aqueous phase was removed and the organic phase was sequentially washed with saturated aqueous NaHCO₃ (100 mL), and saturated aqueous NaCl (100 mL). The organic phase was dried over MgSO₄, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (3% MeOH/CH₂Cl₂) to afford a thick yellow oil from which was obtained crystalline IV-a (R⁴=cyclopropyl) (3.85 g, 97%) as a white solid: mp 86.6-88° C.; ¹H NMR (300 MHz, acetone-d₆) δ 8.95 (br s, 1H), 7.51 (br s, 1H), 7.43 (br s, 1H), 7.40 (dd, J=8.8, 2.4 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H), 1.49-1.41 (m, 1H), 0.93-0.82 (m, 1H), 0.77-0.74 (m, 1H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −82.96; IR (KBr Pellet) 1696, 1172 cm⁻¹; MS (CI) m/e calc'd for C₁₄H₁₀ClF₃N₂O: 315.051201, found 315.051626; 315 (MH⁺, 51), 332 (M+NH₄ ⁺, 100); Analysis calc'd for C₁₄H₁₀N₂ClF₃O. 0.25 H₂O: C, 52.68; H, 3.32; N, 8.78; found: C, 52.61; H, 3.35; N, 8.28.

Example 2 Preparation of (+/−)-6-Chloro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=Isopropyl)

A solution of III-a (50 mg, 0.201 mmol) was treated with the lithium acetylide derived from 3-methyl-1-butyne (62 mg, 93 mL, 0.905 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by flash chromatography (35% EtOAc/hexanes) to afford 26mg (41%) of the desired product: ¹H NMR (300 MHz, ) δ 9.08 (br s, 1H), 7.59 (br s, 1H), 7.53 (br s, 1H), 7.40 (dd, J=8.4, 2.2 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H), 2.81-2.68 (m, 1H), 1.20 (dd, J=6.6 Hz, 6H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −83.05; MS (CI) m/e calc'd for C₁₄H₁₂ClF₃N₂O: 317.066851, found 317.069433; 317 (MH⁺, 43), 334 (M+NH₄ ⁺, 100).

Example 3 Preparation of (+/−)-6-Chloro-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=2-Pyridyl)

A solution of III-a (100 mg, 0.402 mmol) was treated with the the lithium acetylide derived from 2-ethynylpyridine (0.19 g, 1.81 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by HPLC (2.5% MeOH/CH₂Cl₂) to afford 85 mg (60%) of the desired product: mp 105° C. dec.; ¹H NMR (300 MHz, acetone-d₆) δ 9.14 (br s, 1H), 8.64-8.61 (m, 1H), 7.89-7.84 (m, 2H), 7.70-7.66 (m, 2H), 7.48-7.43 (m, 2H), 7.09 (d, J=8.8 Hz, 1H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −82.48; IR (KBr Pellet) 1704, 1430, 1186 cm⁻¹; MS (CI) m/e calc'd for C₁₆H₁₀ClF₃N₃O: 352.046450, found 352.046956; 352 (MH⁺, 100); Analysis calc'd for C₁₆H₉ClF₃N₃O. 0.125 H₂O: C, 54.3; H, 2.56; N, 11.9; found: C, 54.71; H, 3.03; N, 11.3.

Example 4 Preparation of (+/−)-6-Chloro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=Ethyl)

A solution of III-a (100 mg, 0.402 mmol) was treated with the the lithium acetylide derived from 1-butyne (109 mg, 2.01 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by HPLC (2.5% MeOH/CH₂Cl₂) to afford 79 mg (65%) of the desired product: ¹H NMR (300 MHz, acetone-d₆) δ 9.05 (br s, 1H), 7.54 (br s, 2H), 7.41-7.39 (m, 1H), 7.02 (d, J=8.4 Hz, 1H), 2.36-2.32 (m, 2H), 2.18-1.13 (m, 3H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −82.99; MS (CI) m/e calc'd for C₁₃H₁₀ClF₃N₂O: 303.051201, found 303.051882; 303 (MH⁺, 55), 320 (M+NH₄ ⁺, 100).

Example 5 Preparation of (+/−)-6-Chloro-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=Phenyl)

A solution of III-a (100 mg, 0.402 mmol) was treated with the the lithium acetylide derived from phenylacetylene (185 mg, 1.81 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by HPLC (2.5% MeOH/CH₂Cl₂) to afford 54 mg (38%) of the desired product: ¹H NMR (300 MHz, acetone-d₆) δ 9.07 (br s, 1H), 7.74 (br s, 1H), 7.67 (br s, 1H), 7.62-7.58 (m, 2H), 7.48-7.40 (m, 4H), 7.08 (d, J=8.4 Hz, 1H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −82.67; IR (KBr Pellet) 1696, 1186 cm⁻¹; MS (CI) m/e calc'd for C₁₇H₁₁ClF₃N₂O: 351.051201, found 351.051704; 351 (MH⁺, 51), 368 (M+NH₄ ⁺, 100); Analysis calc'd for C₁₇H₁₀ClF₃N₂O. 0.25 H₂O: C, 57.48; H, 2.98; N, 7.89; found: C, 57.00; H, 3.03; N, 7.48.

Example 6 Preparation of (+/−)-4-Cyclopropylethynyl-6-methoxy-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=Cyclopropyl)

Step 1. Synthesis of VI-a from V-a.

A solution of V-a (0.50 g, 2.28 mmol) was treated with dimethylaminopyridine and trimethylsilyl isocyanate as described in Step 1 of Example 1 to afford 0.58 g (97%) of the desired product: ¹H NMR (300 MHz, acetone-d₆) δ 8.81 (br s, 1H), 7.17 (br s, 1H), 7.11 (br s, 1H), 7.00-6.92 (m, 2H), 6.83 (s, 1H), 3.76 (s, 3H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −85.99.

Step 2. Synthesis of VII-a from VI-a.

A solution of VI-a (0.58 g, 2.21 mmol) was heated in toluene at reflux as described in Step 2 of Example 1 to afford 0.50 g (93%) of the desired product: ¹H NMR (300 MHz, acetone-d₆) δ 7.52 (br s, 2H), 7.27 (s, 1H), 3.90 (s, 3H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −68.08.

Step 3. Synthesis of VIII-a from VII-a.

A solution of VII-a (100 mg, 0.410 mmol) was treated with the the lithium acetylide derived from cyclopropylacetylene (0.41 mL of 30 wt % solution in toluene/THF/hexanes, 1.85 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by HPLC (2.5% MeOH/CH₂Cl₂) to afford 103 mg (81%) of the desired product: ¹H NMR (300 MHz, acetone-d₆) δ 8.77 (br s, 1H), 7.29 (br s, 1H), 7.06 (br s, 1H), 6.99-6.90 (m, 2H), 3.77 (s, 3H), 1.46-1.38 (m, 1H), 0.91-0.85 (m, 2H), 0.79-0.72 (m, 2H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −82.61; MS (CI) m/e calc'd for C₁₅H₁₄F₃N₂O₂: 311.100738, found 311.099970; 311 (MH⁺, 100).

Example 7 Preparation of (+/−)-4-Isopropylethynyl-6-methoxy-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=Isopropyl)

A solution of VII-a (100 mg, 0.410 mmol) was treated with the the lithium acetylide derived from 3-methyl-1-butyne (126 mg, 0.19 mL, 1.85 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by flash chromatography (2.5% MeOH/CH₂Cl₂) to afford 30 mg (24%) of the desired product: mp 228-229° C.; ¹H NMR (300 MHz, acetone-d₆) δ 8.72 (br s, 1H), 7.27 (br s, 1H), 7.10 (br s, 1H), 7.00-6.91 (m, 2H), 3.77 (s, 3H), 2.73-2.67 (m, 1H), 1.20 (dd, J=7.0, 1.5 Hz, 6H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −82.71; IR (KBr Pellet) 1696, 1428, 1190, 1176 cm⁻¹; MS (CI) m/e calc'd for C₁₅H₁₆F₃N₂O₂: 313.116388, found 313.115871; 313 (MH⁺, 100), 330 (M+NH₄ ⁺, 15); Analysis calc'd for C₁₅H₁₅F₃N₂O₂: C, 57.69; H, 4.84; N, 8.97; found: C, 57.74; H, 5.01; N, 8.57.

Example 8 Preparation of (+/−)-6-Methoxy-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=2-Pyridyl)

A solution of VII-a (100 mg, 0.410 mmol) was treated with the the lithium acetylide derived from 2-ethynylpyridine (0.19 g, 1.85 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by flash chromatography (2.5% MeOH/CH₂Cl₂) to afford 56 mg (39%) of the desired product: ¹H NMR (300 MHz, acetone-d₆) δ 8.81 (br s, 1H), 8.61 (d, J=4.8 Hz, 1H), 7.88-7.82 (m, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.61 (br s, 1H), 7.46-7.42 (m, 1H), 7.23 (br s, 1H), 7.06-6.97 (m, 2H), 3.79 (s, 3H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −82.13; IR (KBr Pellet) 1698, 1518, 1464, 1430, 1244, 1208, 1184 cm⁻¹; MS (CI) m/e calc'd for C₁₇H₁₃F₃N₃O₂: 348.095987, found 348.095629; 348 (MH⁺, 100); Analysis calc'd for C₁₇H₁₂F₃N₃O₂ . 0.25 C₃H₆O: C, 58.92; H, 3.76; N. 11.61; found: C, 59.38; H, 4.04; N, 11.35.

Example 9 Preparation of (+/−)-6-Methoxy-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=Phenyl)

A solution of VII-a (100 mg, 0.410 mmol) was treated with the the lithium acetylide derived from phenylacetylene (0.19 g, 1.85 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by flash chromatography (2.5% MeOH/CH₂Cl₂) to afford 34 mg (24%) of the desired product: mp 206.2-207.7° C.; ¹H NMR (300 MHz, acetone-d₆) δ 8.85 (br s, 1H), 7.60-7.57 (m, 3H), 7.49-7.39 (m, 3H), 7.21 (br s, 1H), 7.05-6.96 (m, 2H), 3.79 (s, 3H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −82.32; IR (KBr Pellet) 1696, 1516, 1430, 1236, 1204, 1184, 1128 cm⁻¹; MS (CI) m/e calc'd for C₁₈H₁₄F₃N₂O₂: 347.100738, found 347.101482; 347 (MH⁺, 100), 364 (M+NH₄ ⁺, 48); Analysis calc'd for C₁₈H₁₃F₃N₂O₂: C, 62.43; H, 3.78; N, 8.10; found: C, 62.35; H, 3.58; N, 7.83.

Example 10 Preparation of (+/−)-4-Cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=Cyclopropyl)

Step 1. Synthesis of X-a from IX-a.

A solution of IX-a (6.46 g, 28.7 mmol) was treated with dimethylaminopyridine and trimethylsilyl isocyanate as described in Step 1 of Example 1 to afford 6.74 g (88%) of the desired product: ¹H NMR (300 MHz, acetone-d₆) δ 9.13 (br s, 1H), 7.45-7.32 (m, 2H), 7.18 (br s, 1H), 6.85-6.80 (m, 1H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −86.6 (d, 17.2, 3), −137.52-137.68 (m, 1), −148.47-148.59 (m, 1).

Step 2. Synthesis of XI-a from X-a.

A solution of X-a (6.74 g, 25.1 mmol) was heated in xylenes at reflux as described in Step 2 of Example 1, substituting xylenes for toluene, to afford 6.3 g (100%) of the desired product: ¹H NMR (300 MHz, acetone-d₆) δ 7.92-7.83 (m, 1H), 7.46-7.44 (m, 1H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −70.7 (d, 38.7, 3), −136.72 (s, 1), −146.47-146.57 (m, 1).

Step 3. Synthesis of XII-a from XI-a.

A solution of XI-a (6.28 g, 25.1 mmol) was treated with the the lithium acetylide derived from cyclopropylacetylene (24.9 mL of 30 wt % solution in toluene/THF/hexanes, 0.113 mol) according to the procedure of Step 3 of Example 1. The resulting crude yellow oil was dissolved in acetone and concentrated under reduced pressure to deliver a yellow solid. Crystallization from acetone afforded 5.98 g (75%) of the desired material: mp 86.5-88.5° C.; ¹H NMR (300 MHz, acetone-d₆) δ 9.01 (br s, 1H), 7.46 (br s, 1H), 7.44-7.35 (m, 1H), 6.86-6.81 (m, 1H), 1.41-1.37 (m, 1H), 0.90-0.83 (m, 1H), 0.74-0.69 (m, 1H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −83.3 (d, J=12.9, 1), −136.04-136.23 (m, 1), −148.14-148.26 (m, 1); IR (KBr Pellet) 1706, 1516, 1442, 1246, 1214, 1196 cm⁻¹; MS (CI) m/e calc'd for C₁₄H₁₀F₅N₂O: 317.071329, found 317.070836; 317 (MH⁺, 100), 334 (M+NH₄ ⁺, 62); Analysis calc'd for C₁₄H₉F₅N₂O: C, 53.17; H, 2.88; N, 8.87; found: C, 53.30; H, 3.16; N, 8.53.

Example 11 Preparation of (+/−)-5,6-Difluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=Isopropyl)

A solution of XI-a (7.24 g, 28.9 mmol) was treated with the the lithium acetylide derived from 3-methyl-1-butyne (8.87 g, 13.3 mL, 0.130 mol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by flash chromatography (2.5% MeOH/CH₂Cl₂) to afford a yellow oil. Crystallization from acetone afforded 6.77 g (74%) of the desired product: mp 79-80° C.; ¹H NMR (300 MHz, acetone-d₆) δ 9.02 (br s, 1H), 7.50 (br s, 1H), 7.44-7.35 (m, 1H), 6.87-6.82 (m, 1H), 2.69-2.65 (m, 1H), 1.17 (d, J=7.0 Hz, 6H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −83.4 (d, J=12.9, 1), −135.79-135.94 (m, 1), −148.14-148.26 (m, 1); MS (CI) m/e calc'd for C₁₄H₁₂F₅N₂O: 319.086979, found 319.087376; 319 (MH⁺, 100), 336 (M+NH₄ ⁺, 76).

Example 12 Preparation of (+/−)-5,6-Difluoro-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=2-Pyridyl)

A solution of XI-a (100 mg, 0.400 mmol) was treated with the the lithium acetylide derived from 2-ethynylpyridine (0.19 g, 1.80 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by flash chromatography (4% MeOH/CH₂Cl₂) to afford 83 mg (59%) of the desired product: mp 219-220° C.; ¹H NMR (300 MHz, acetone-d₆) δ 9.15 (br s, 1H), 8.61 (d, J=4.4 Hz, 1H), 7.88-7.82 (m, 2H), 7.63 (dd, J=7.0, 1.1 Hz, 1H), 7.47-7.42 (m, 2H), 6.94-6.88 (m, 1H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −82.8 (d, J=12.9, 3), −135.78-135.93 (m, 1), −147.86-147.98 (m, 1); IR (KBr Pellet) 1712, 1470, 1450, 1430, 1416, 1264, 1238, 1226, 1198, 1186 cm⁻¹; MS (CI) m/e calc'd for C₁₆H₉F₅N₃O: 354.066578, found 354.067821; 354 (MH⁺, 100).

Example 13 Preparation of (+/−)-5,6-Difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=2-Ethyl)

A solution of XI-a (100 mg, 0.400 mmol) was treated with the the lithium acetylide derived from 1-butyne (97 mg, 1.80 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by HPLC (2.5% MeOH/CH₂C₂) to afford 69 mg (57%) of the desired product: mp 191-194° C.; ¹H NMR (300 MHz, acetone-d₆) δ 9.03 (br s, 1H), 7.50 (br s, 1H), 7.45-7.35 (m, 1H), 6.87-6.82 (m, 1H), 2.34-2.27 (m, 2H), 1.20-1.15 (m, 3H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −83.3 (d, J=12.9, 3), −135.79-135.98 (m, 1), −148.16-148.29 (m, 1); IR (KBr Pellet) 1704, 1686, 1518, 1444, 1244, 1210, 1192, 1172 cm⁻¹; MS (CI) m/e calc'd for C₁₃H₁₀F₅N₂O: 305.071329, found 305.071146; 305 (MH⁺, 100); Analysis calc'd for C₁₃H₉F₅N₂O: C, 51.33; H, 2.98; N, 9.22; found: C, 51.00; H, 2.79; N, 8.99.

Example 14 Preparation of (+/−)-5,6-Difluoro-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=Phenyl)

A solution of XI-a (100 mg, 0.400 mmol) was treated with the the lithium acetylide derived from phenylacetylene (0.18 g, 0.20 mL, 1.80 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by HPLC (2.5% MeOH/CH₂Cl₂) to afford 92 mg (65%) of the desired product: ¹H NMR (300 MHz, acetone-d₆) δ 9.14 (br s, 1H), 7.80 (br s, 1H), 7.57-7.54 (m, 2H), 7.49-7.40 (m, 4H), 6.92-6.87 (m, 1H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −83.0 (d, J=12.9, 3), −136.08-136.27 (m, 1), −147.87-148.00 (m, 1); MS (CI) m/e calc'd for C₁₇H₁₀F₅N₂O: 353.071329, found 353.071716; 353 (MH⁺, 42), 370 (M+NH₄ ⁺, 100).

Example 15 Preparation of (+/−)-5,6-Difluoro-4-isopentyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=Isopropyl)

Synthesis of XIII-a from XII-a.

A solution of XIII-a (R⁴=isopropyl) (26 mg, 82 mmol) in ethanol (1 mL) and EtOAc (0.5 mL) was treated with 10% Pd on carbon (35 mg) under H₂ (1 atm) for 16 hours. The catalyst was removed by vacuum filtration through Celite and the filter cake was washed with EtOAc. The combined filtrates were concentrated under reduced pressure to afford 26 mg (100%) of the desired material. No further purification was necessary: ¹H NMR (300 MHz, acetone-d₆) δ 8.88 (br s, 1H), 7.41-7.31 (m, 1H), 6.89-6.81 (m, 2H), 2.55-2.50 (m, 1H), 1.64-1.45 (m, 2H), 1.06-1.02 (m, 1H), 0.89 (dd, J=6.6, 2.2 Hz, 6H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −83.22 (d, J=12.1, 3), −138.97-139.13 (m, 1), −148.46-148.58 (m, 1); IR (KBr Pellet) 1700, 1678, 1518, 1438, 1252, 1188, 1172 cm⁻¹; MS (CI) m/e calc'd for C₁₄H₁₆F₅N₂O: 323.118280, found 323.116703; 323 (MH⁺, 100), 340 (M+NH₄ ⁺, 57).

Example 16 Preparation of (+/−)-4-Butyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=Ethyl)

A solution of XIII-a (R⁴=ethyl) (20 mg, 66 mmol) in ethanol (1 mL) and EtOAc (0.5 mL) was treated with 10% Pd on carbon under H₂ according to the procedure of Example 15. Purification by HPLC (2.5% MeOH/CH₂Cl₂) afforded 12 mg (56%) of the desired product: ¹H NMR (300 MHz, acetone-d₆) δ 8.89 (br s, 1H), 7.41-7.32 (m, 1H), 6.86-6.81 (m, 2H), 2.57-2.47 (m, 1H), 1.56-1.15 (m, 5H), 0.88 (t, J=7.3 Hz, 3H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −83.19-83.24 (m, 1), −139.14 (s, 1), −148.49-148.62 (m, 1); MS (CI) m/e calc'd for C₁₃H₁₄F₅N₂O: 309.102629, found 309.103555; 309 (MH⁺, 100), 326 (M+NH₄ ⁺, 62).

Example 17 Preparation of (+/−)-4-Cyclopropylethynyl-6-fluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=Cyclopropyl)

Step 1. Synthesis of XV-a from XIV-a.

A solution of XIII-a (3.07 g, 14.8 mmol) was treated with dimethylaminopyridine and trimethylsilyl isocyanate as described in Step 1 of Example 1 to afford 2.81 g (76%) of the desired product.

Step 2. Synthesis of XVI-a from XV-a.

A solution of XV-a (6.74 g, 25.1 mmol) was heated in toluene at reflux as described in Step 2 of Example 1 to afford 0.73 g (94%) of the desired product.

Step 3. Synthesis of XVII-a from XVI-a.

A solution of XVI-a (100 mg, 0.431 mmol) was treated with the the lithium acetylide derived from cyclopropylacetylene (1.43 mL of 30 wt % solution in toluene/THF/hexanes, 1.94 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by HPLC (2.5% MeOH/CH₂Cl₂) to afford 44 mg (34%) of the desired product: mp 155° C.; ¹H NMR (300 MHz, acetone-d₆) δ 8.86 (br s, 1H), 7.36 (br s, 1H), 7.30-7.27 (m, 1H), 7.22-7.15 (m, 1H), 7.04-6.99 (m, 1H), 1.47-1.42 (m, 1H), 0.90-0.87 (m, 2H), 0.76-0.75 (m, 2H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −82.86, −123.36-123.44; MS (CI) mle calc'd for C₁₄H₁₁F₄N₂O: 299.080751, found 299.079976; 299 (MH⁺, 100).

Example 18 Preparation of (+/−)-6-Fluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=Isopropyl)

A solution of XVI-a (100 mg, 0.431 mmol) was treated with the the lithium acetylide derived from 3-methyl-1-butyne (0.13 g, 0.20 mL, 1.94 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by HPLC (2.5% MeOH/CH₂Cl₂) to afford 24 mg (18%) of the desired product: mp 158° C.; ¹H NMR (300 MHz, acetone-d₆) δ 9.07 (br s, 1H), 7.60 (br s, 1H), 7.32-7.30 (m, 1H), 7.24-7.16 (m, 1H), 7.05-6.99 (m, 1H), 2.77-2.67 (m, 1H), 1.20 (dd, J=7.0, 2.6 Hz, 6H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −82.95, −123.41-123.49; MS (301) m/e calc'd for C₁₄H₁₃F₄N₂O: 301.096401, found 301.096235; 301 (MH⁺, 100).

Example 19 Preparation of (+/−)-6-Fluoro-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=2-Pyridyl)

A solution of XVI-a (100 mg, 0.431 mmol) was treated with the the lithium acetylide derived from 2-ethynylpyridine (0.20 g, 1.94 mnol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by HPLC (2.5% MeOH/CH₂Cl₂) to afford 65 mg (45%) of the desired product: mp 155° C.; ¹H NMR (300 MHz, acetone-d₆) δ 9.02 (br s, 1H), 8.60 (d, J=4.0 Hz, 1H), 7.87-7.78 (m, 2H), 7.66 (d, J=7.7 Hz, 1H), 7.45-7.41 (m, 2H), 7.26-7.20 (m, 1H), 7.09-7.05 (m, 1H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −82.36, −122.94-123.02; MS (CI) m/e calc'd for C₁₆H₁₀F₄N₃O: 336.076000, found 336.074156; 336 (MH⁺, 25).

Example 20 Preparation of (+/−)-6-Fluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(lH)-quinazolinone (R⁴=Ethyl)

A solution of XVI-a (100 mg, 0.431 mmol) was treated with the the lithium acetylide derived from 1-butyne (0.10 g, 1.94 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by HPLC (2.5% MeOH/CH₂Cl₂) to afford 40 mg (33%) of the desired product: mp 190° C.; ¹H NMR (300 MHz, acetone-d₆) δ 8.86 (br s, 1H), 7.38 (br s, 1H), 7.34-7.31 (m, 1H), 7.22-7.16 (m, 1H), 7.05-7.00 (m, 1H), 2.04-2.01 (m, 2H), 1.19-1.14 (m, 3H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −75.392, −123.42-123.50; MS (CI) m/e calc'd for C₁₃H₁₁F₄N₂O: 287.080751, found 287.080740; 287 (MH⁺, 100).

Example 21 Preparation of (+/−)-6-Fluoro-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=Phenyl)

A solution of XVI-a (100 mg, 0.431 mmol) was treated with the the lithium acetylide derived from phenylacetylene (0.20 g, 0.21 mL, 1.94 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by HPLC (2.5% MeOH/CH₂Cl₂) to afford 41 mg (28%) of the desired product: mp 107° C.; ¹H NMR (300 MHz, acetone-d₆) δ 9.00 (br s, 1H), 7.69 (br s, 1H), 7.63-7.59 (m, 2H), 7.50-7.40 (m, 4H), 7.27-7.20 (m, 1H), 7.10-7.05 (m, 1H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −82.56, −122.99-123.07; MS (CI) m/e calc'd for C₁₇H₁₁F₄N₂O: 335.080751, found 335.082057; 335 (MH⁺, 74), 352 (M+NH₄ ⁺, 100).

Example 22 Preparation of (+/−)-6-Fluoro-4-isopentyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=Isopropyl)

Synthesis of XVIII-a from XVII-a.

A solution of XVII-a (R⁴=isopropyl) (26 mg, 87 mmol) in ethanol (1 mL) and EtOAc (0.5 mL) was treated with 10% Pd on carbon under H₂ according to the procedure of Example 15 to afford 15 mg (58%) of the desired product. No further purification was necessary: mp 179° C.; ¹H NMR (300 MHz, acetone-d₆) δ 7.02-6.97 (m, 2H), 6.80-6.76 (m, 1H), 2.18-2.09 (m, 2H), 1.92-1.82 (m, 2H), 1.52-1.45 (m, 1H), 0.88-0.79 (m, 6H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −82.60, −123.72-123.84; MS (CI) m/e calc'd for C₁₄H₁₇F₄N₂O: 305.127707, found 305.126790; 305 (MH⁺, 100).

Example 23 Preparation of (+/−)-6-Fluoro-4-(2′-2-pyridyl)ethyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=2-Pyridyl)

A solution of XVII-a (R⁴=2-pyridyl) (33 mg, 99 mmol) in ethanol (1 mL) and EtOAc (0.5 mL) was treated with 10% Pd on carbon under H₂ according to the procedure of Example 15 to afford 10 mg (30%) of the desired product. No further purification was necessary: mp 88° C.; ¹H NMR (300 MHz, acetone-d₆) δ 8.35 (d, J=4.4 Hz, 1H), 7.63 (dt, J=7.7, 1.5 Hz, 1H), 7.20-7.13 (m, 3H), 7.04-6.98 (m, 1H), 6.83-6.79 (m, 1H), 2.84-2.78 (m, 1H), 2.68-2.48 (m, 2H), 2.27-2.06 (m, 1H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −82.58, −123.26-123.34; MS (CI) m/e calc'd for C₁₆H₁₄F₄N₃O: 340.107300, found 340.107719; 340 (MH⁺, 100).

Example 24 Preparation of (+/−)-4-Butyl-6-fluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=Ethyl)

A solution of XVII-a (R⁴=ethyl) (24 mg, 84 mmol) in ethanol (1 mL) and EtOAc (0.5 mL) was treated with 10% Pd on carbon under H₂ according to the procedure of Example 15 to afford 24 mg (100%) of the desired product. No further purification was necessary: mp 198° C.; ¹H NMR (300 MHz, acetone-d₆) δ 7.03-6.97 (m, 2H), 6.80-6.76 (m, 1H), 2.18-2.11 (m, 1H), 1.90-1.81 (m, 1H), 1.30-1.19 (m, 3H), 0.97-0.80 (m, 4H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −82.692, −123.78-123.86; MS (CI) m/e calc'd for C₁₃H₁₅F₄N₂O: 291.112051, found 291.112227; 291 (MH⁺, 100).

Example 25 Preparation of (+/−)-6-Fluoro-4-phenylethyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R⁴=Phenyl)

A solution of XVII-a (R⁴=phenyl) (30 mg, 90 mmol) in ethanol (1 mL) and EtOAc (0.5 mL) was treated with 10% Pd on carbon under H₂ according to the procedure of Example 15 to afford 20 mg (67%) of the desired product. No further purification was necessary: mp 98° C.; ¹H NMR (300 MHz, acetone-d₆) δ 7.18-6.99 (m, 7H), 6.84-6.79 (m, 1H), 2.68-2.60 (m, 1H), 2.48-2.12 (m, 3H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −82.67, −123.24-123.32; MS (CI) m/e calc'd for C₁₇H₁₅F₄N₂O: 339.112051, found 339.110781; 339 (MH⁺, 100).

Example 26 Preparation of (+/−)-6-Fluoro-4-methylpropargyl-4-trifluoromethyl-3,4-dihydro-2(1H)-guinazolinone (R⁴=Methyl)

Synthesis of XIX-a from XVI-a.

A solution of 2-butyne (94 mg, 1.75 mmol) in anhydrous THF (3.5 mL) was cooled to 0° C., treated with n-BuLi (0.97 mL of 1.6 M solution in hexanes, 1.55 mmol), and aged for 0.5 h. To a solution of XVI-a (90 mg, 0.388 mml) in anhydrous THF (1.9 mL) at −78° C. was added the lithium anion over 5 minutes, followed by boron trifluoride etherate (25 mL, 0.194 mmol). The cooling bath was removed and the mixture was allowed to warm to room temperature. After 16 h at room temperature, quench by addition of 1 M citric acid (10 mL), dilute with EtOAc (50 mL), separate phases and wash the organic phase sequentially with saturated aqueous NaHCO₃ (20 mL) and saturated aqueous NaCl (20 mL). The resulting material was purified by HPLC (2.5% MeOH/CH₂Cl₂) to afford 10 mg (9%) of the desired product: mp 181° C.; ¹H NMR (300 MHz, acetone-d₆) δ 8.91 (br s, 1H), 7.27 (d, 8.4H), 7.18-7.08 (m, 1H), 7.02-6.97 (m, 2H), 3.29 (dd, J=16.8, 2.6 Hz, 1H), 3.00 (dd, J=16.8, 2.2 Hz, 1H), 1.61-1.59 (m, 3H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −81.86, −123.69-123.70; MS (CI) m/e calc'd for C₁₃H₁₁F₄N₂O: 287.080751, found 287.080340; 287 (MH⁺, 75), 304 (M+NH₄ ⁺, 100).

SCHEME 4: Chiral Resolution

R³ Compound R³ Compound R³ Compound 6-Cl IV-a 6-Cl IV-b 6-Cl IV-c 6-MeO VIII-a 6-MeO VIII-b 6-MeO VIII-c 5,6-diF XII-a 5,6-diF XII-b 5,6-diF XII-c 6-F XVII-a 6-F XVII-b 6-F XVII-c

Examples 27 and 28 Preparation of (−)-6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (Example 27) and (+)-6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-guinazolinone (Example 28)

Resolution of IV-b,c from IV-a (R⁴=Cyclopropyl).

Chiral HPLC utilizing a Chiralcel OD column, 3% isopropanol, 5% CH₂Cl₂ and 92% hexanes at ambient temperature with a 1.0 mL/min flow rate and detection at 250 nm afforded seperation of IV-b from IV-c with enantiomeric excesses of 99% and 99.4%, respectively. IV-b: mp 106-109° C.; [α]_(D) ²⁵ −60.34° (c=0.274, MeOH). IV-c: mp105-107° C.; [α]_(D) ²⁵ +58.33° (c=0.288, MeOH).

Examples 29 and 30 Preparation of (+)-4-Cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (Example 29) and (−)-4-Cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2 (1H)-quinazolinone (Example 30)

Resolution of XII-b,c from XII-a (R⁴=Cyclopropyl).

Chiral HPLC utilizing a Chiralpak AD column, 5% water and 95% methanol at ambient temperature with a 0.8 mL/min flow rate and detection at 250 nm afforded seperation of XII-b from XII-c with enantiomeric excesses of 100% and 99%, respectively. XII-b: mp 187° C.; [α]_(D) ²⁵ +1.46° (c=0.274, MeOH). XII-c: mp 187.5-188.8° C.; [α]_(D) ²⁵ −1.45° (c=0.278, MeOH).

Examples 31 and 32 Preparation of (−)-5,6-Difluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (Example 31) and (+)-5,6-Difluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H)-quinazolinone (Example 32)

Resolution of XII-b,c from XII-a (R⁴=Isopropyl).

Chiral HPLC utilizing a Chiralpak AD column, 5% water and 95% methanol at ambient temperature with a 0.5 mL/min flow rate and detection at 250 nm afforded seperation of XII-b from XII-c with enantiomeric excesses of 100% and 99%, respectively. XII-b: mp 155° C.; [α]_(D) ²⁵ −2.140 (c=0.280, MeOH). XII-c: 98° C.; [α]_(D) ²⁵ +4.450 (c=0.292, MeOH)

Examples 33 and 34 Preparation of (−)-5,6-Difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (Example 33) and (+)-5,6-Difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H)-quinazolinone (Example 34)

Resolution of XII-b,c from XII-a (R⁴=Ethyl).

Chiral HPLC utilizing a AS column, 20% ethanol and 80% hexanes at ambient temperature with a 1.0 mL/min flow rate and detection at 250 nm afforded seperation of XII-b from XII-c with enantiomeric excesses of 100% and 99%, respectively. XII-b: mp 165-167° C. XII-c: mp 157-159° C.

Examples 35 and 36 Preparation of 5,6-Difluoro-4-(2-hydroxyethyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (Example 35) and 5,6-Difluoro-4-(1-hydroxyethyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H)-quinazolinone (Example 36)

Compound R Compound R Ex. 35 CH₂CH₂OTBS Ex. 35 CH₂CH₂OH Ex. 36 CH(OTBS)CH₃ Ex. 36 CH(OH)CH₃

To a slurry of ketimine (300 mg, 1.20 nmol) in anhyd. THF (11 mL) at −78° C. was sequentially added a precooled (0° C.) solution of the silyl protected lithium acetylide (5.40 nmmol) and BF3.OEt2 (0.60 mmol). The resulting mixture was stirred at rt overnight. The reaction was quenched by the addition of 1 M citric acid and diluted with EtOAc. The phases were separated, the organic phase was washed with water, sat. aq. NaHCO3 and sat. aq. NaCl. The organic extracts were dried over MgSO4, filtered and concentrated. The material was purified by regular phase HPLC chromatography (41.4 mm Rainin Dynamax® column using 60 Å silica @25 mL/min): 2.5% MeOH/CH₂Cl₂ for 24 min, increase to 30% MeOH/CH₂Cl₂ over 4 min, 30% MeOH/CH₂Cl₂ for 10 min, and ramp back to 2.5% MeOH/CH2Cl2 over 2 min. The yield of the protected intermediates was 47% and 32%, respectively.

Example 35-intermediate. Mp 62.9-64° C.; ¹H NMR (300 MHz, acetone-d₆) δ 8.98 (br s, 1H), 7.41-7.32 (m, 2H), 6.83-6.78 (m, 1H), 3.74 (t, J=6.6 Hz, 2H), 2.47 (t, J=6.6 Hz, 2H), 0.81 (s, 9H), 0.00 (s, 6H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −83.17, −135.16-−135.31, −148.09-−148.22; MS (CI) calc'd for C19H24F5N2O2Si: m/z 435.152723, found 435.151149; 435 (MH+, 94), 452 (M+NH4+, 100); Analysis calc'd for C₁₉H₂₃F₅N₂O₂Si: C, 52.52; H, 5.35; N, 6.46; found: C, 52.65; H, 5.29; N, 6.31.

Example 36-intermediate. ¹H NMR (300 MHz, acetone-d₆) δ 8.96 (br s, 1H), 7.50 (br s, 1H), 7.37-7.28 (m, 1H), 6.79-6.74 (m, 1H), 4.61 (q, J=13.2, 6.6 Hz, 1H), 1.30 (d, J=6.6 Hz, 3H), 0.78 (s, 9H), 0.01 (s, 6H); ¹⁹F NMR (282 MHz, acetone-d₆) d −82.88-−82.95, −135.20-−135.42, −148.06-−148.23; MS (CI) calc'd for C19H24F5N2O2Si: m/z 435.152723, found 435.152927; 435 (MH+, 51), 452 (M+NH4+, 100); Analysis calc'd for C₁₉H₂₃F₅N₂O₂Si: C, 52.52; H, 5.35; N, 6.46; found: C, 52.54; H, 5.34; N, 6.69.

To a solution of the protected intermediate for Example 35 (0.56 mmol) in THF (1.1 mL) was added TBAF (0.62 mL of 1.0 M solution in THF). The resulting mixture was stirred at rt for 1 h, diluted with EtOAc, washed with 1 N HCl, sat. aq. NaHCO₃, and sat. aq. NaCl. The organic extract was dried over MgSO₄, filtered and concentrated. The material was purified by regular phase HPLC chromatography (41.4 mm Rainin Dynamax® column using 60 Å silica @25 mL/min): 2.5% MeOH/CH₂Cl₂ for 24 min, increase to 30% MeOH/CH₂Cl₂ over 4 min, 30% MeOH/CH₂Cl₂ for 10 min, and ramp back to 2.5% MeOH/CH₂Cl₂ over 2 min. Example 35 was isolated in 82% yield.

Example 35. Mp 190-192° C.; ¹H NMR (300 MHz, acetone-d₆) δ 9.05 (br s, 1H), 7.53 (br s, 1H), 7.45-7.36 (m, 1H), 6.88-6.83 (m, 1H), 4.01-3.98 (m, 1H), 3.68-3.64 (m, 2H), 2.50 (t, J=6.6 Hz, 2H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −83.3, −135.68-−135.88, −148.10-−148.22; MS (CI) calc'd for C₁₃H₁₀F₅N₂O₂: m/z 321.066244, found 321.066479; 321 (MH+, 100); Analysis calc'd for C₁₃H₉F₅N₂O₂: C, 48.76; H, 2.83; N, 8.76; found: C, 49.05; H, 3.23; N, 8.38.

Example 36 was synthesized in an analogous manner to deliver the title compound in 88% yield. Mp 190-191° C.; ¹H NMR (300 MHz, acetone-d₆) δ 9.06 (br s, 1H), 7.56 (br s, 1H), 7.46-7.37 (m, 1H), 6.88-6.83 (m, 1H), 4.58-4.57 (m, 2H), 1.39 (d, J=5.5 Hz, 3H); ¹⁹F NMR (282 MHz, acetone-d₆) δ −83.15, −135.40, −135.60, −148.08-−148.20; MS (CI) calc'd for C₁₃H₁₀F₅N₂O₂: m/z 321.066244, found 321.065983; 321 (MH+, 58), 338 (M+NH4+, 100); Analysis calc'd for C₁₃H₉F₅N₂O₂: C, 48.76; H, 2.83; N, 8.76; found: C, 48.84; H, 2.76; N, 8.63.

Example 37 Preparation of (+)-4-E-Cyclopropylethenyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone

To a solution of XII-b (200 mg, 0.632 mmol) in anhyd. THF (1.3 mL) at rt was added a solution of lithium aluminium hydride (1.3 mL of 1.0 M solution in THF). The resulting mixture was stirred at rt overnight. The reaction was quenched by addition of 10% NaOH (3 mL) and water (3 mL). The mixture was diluted with EtOAc (30 mL) and the phases were separated. The organic phase was washed with sat. aq. NaCl, dried over MgSO₄, filtered and concentrated. The title compound was purified by regular phase HPLC (41.4 mm Rainin Dynamax® column using 60 Å silica): 2.5% MeOH/CH₂Cl₂ for 24 min, increase to 30% MeOH/CH₂Cl₂ over 4 min, 30% MeOH/CH₂Cl₂ for 10 min, and ramp back to 2.5% MeOH/CH₂Cl₂ over 2 min. Mp 80-83° C.; ¹H NMR (300 MHz, acetone-d₆) d 9.07 (br s, 1H), 7.33 (q, J=8.8 Hz, 1H), 6.94 (br s, 1H), 6.84-6.79 (m, 1H), 6.27 (dd, J=15.6, 7.5 Hz, 1H), 5.67 (dd, J=15.2, 9.4 Hz, 1H), 1.65-1.56 (m, 1H), 0.80-0.71 (m, 2H), 0.50-0.42 (m, 2H); ¹⁹F NMR (282 MHz, acetone-d₆) d −82.68, −135.05, −148.49; MS (CI) calc'd for C₁₄H₁₂F₅N₂O: m/z 319.086979, found 319.087755; 319 (MH+, 100); [α]_(D) ²⁰ +72.77° (c=0.382, MeOH); Analysis calc'd for C₁₄H₁₁F₅N₂O: C, 52.84; H, 3.48; N, 8.80; found: C, 53.02; H, 3.48; N, 8.61.

Example 38 Preparation of (−)-6-Chloro-4-E-cyclopropylethenyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone

The title compound was prepared as described for Example 37 (starting from IV-b), except that it was purified using a Chiralcel OD column at 1.5 mL/min in 0.5% EtOH/20% CH₂Cl₂/79.5% hexanes. Mp 87-89° C.; ¹H NMR (300 MHz, acetone-d₆) d 9.08 (br s, 1H), 7.40-7.25 (m, 2H), 7.04-6.90 (m, 2H), 6.28-6.18 (m, 1H), 5.64-5.52 (m, 1H), 1.68-1.55 (m, 1H), 0.83-0.71 (m, 2H), 0.53-0.41 (m, 2H); ¹⁹F NMR (282 MHz, acetone-d₆) d −81.67; MS (CI) calc'd for C₁₄H₁₃ClF₃N₂O: m/z 317.066851, found 317.065857; 317 (MH+, 100); [α]_(D) ²⁰ −6.81° (c=0.382, MeOH); Analysis calc'd for C₁₄H₁₂ClF₃N₂O.0.27 C₃H₆O: C, 53.52; H, 4.13; N, 8.43; found: C, 53.90; H, 4.07; N, 8.80.

TABLE 1*

Ex. # R³ R¹ R² R⁸ m.p. (° C.) Mass Spec  1 6-Cl CF₃ C≡C-cycPr H  86.6-88 332 (M + NH₄ ⁺)  2 6-Cl CF₃ C≡C-iPr H 180 334 (M + NH₄ ⁺)  3 6-Cl CF₃ C≡C-2-Pyridyl H 105 352 (MH⁺)  4 6-Cl CF₃ C≡C—Et H 217-219 303 (MH⁺)  5 6-Cl CF₃ C≡C—Ph H 104-107 368 (M + NH₄ ⁺)  6 6-MeO CF₃ C≡C-cycPr H 208 311 (MH⁺)  7 6-MeO CF₃ C≡C-iPr H 228-229 313 (MH⁺)  8 6-MeO CF₃ C≡C-2-Pyridyl H  97-98 348 (MH⁺)  9 6-MeO CF₃ C≡C—Ph H 206.2-207.7 347 (MH⁺) 10 5,6-diF CF₃ C≡C-cycPr H 101 dec. 317 (MH⁺) 11 5,6-diF CF₃ C≡C-iPr H  79-80 319 (MH⁺) 12 5,6-diF CF₃ C≡C-2-Pyridyl H 219-220 354 (MH⁺) 13 5,6-diF CF₃ C≡C—Et H 191-194 305 (MH⁺) 14 5,6-diF CF₃ C≡C—Ph H 215-217 370 (M + NH₄ ⁺) 15 5,6-diF CF₃ CH₂CH₂CH(CH₃)₂ H 192-193 323 (MH⁺) 16 5,6-diF CF₃ CH₂CH₂CH₂CH₃ H 309 (MH⁺) 17 6-F CF₃ C≡C-cycPr H 155 299 (MH⁺) 18 6-F CF₃ C≡C-iPr H 158 301 (MH⁺) 19 6-F CF₃ C≡C-2-Pyridyl H 155 336 (MH⁺) 20 6-F CF₃ C≡C—Et H 190 287 (MH⁺) 21 6-F CF₃ C≡C—Ph H 107 352 (M + NH₄ ⁺) 22 6-F CF₃ CH₂CH₂CH(CH₃)₂ H 179 305 (MH⁺) 23 6-F CF₃ CH₂CH₂-2-Pyridyl H  88 340 (MH⁺) 24 6-F CF₃ CH₂CH₂CH₂CH₃ H 198 291 (MH⁺) 25 6-F CF₃ CH₂CH₂Ph H  98 339 (MH⁺) 26 6-F CF₃ CH₂C≡C—CH₃ H 181 304 (M + NH₄ ⁺) 27 (−) 6-Cl CF₃ C≡C-cycPr H 106-109 313 (M⁻) 28 (+) 6-Cl CF₃ C≡C-cycPr H 105-107 313 (M⁻) 29 (+) 5,6-diF CF₃ C≡C-cycPr H 187 315 (M⁻) 30 (−) 5,6-diF CF₃ C≡C-cycPr H 188-189 315 (M⁻) 31 (−) 5,6-diF CF₃ C≡C-iPr H 155 317 (M⁻) 32 (+) 5,6-diF CF₃ C≡C-iPr H  98 317 (M⁻) 33 (−) 5,6-diF CF₃ C≡C—Et H 165-167 303 (M⁻) 34 (+) 5,6-diF CF₃ C≡C—Et H 157-159 303 (M⁻) 35 5,6-diF CF₃ C≡CCH₂CH₂OH H 190-192 321 (MH⁺) 36 5,6-diF CF₃ C≡C—CH(OH)Me H 190-191 338 (M + NH₄ ⁺) 37 (+) 5,6-diF CF₃ C═C-cycPr (E) H  80-83 319 (MH⁺) 38 (−) 6-Cl CF₃ C═C-cycPr (E) H  87-89 317 (MH⁺) *Unless otherwise indicated, stereochemistry is (+/−).

TABLE 2

Ex. # R³ R¹ R² R⁸ 1 6-Cl CF₃ C≡CCH₂CH₂OH H 2 6-Cl CF₃ C≡C—CH(OH)Me H 3 6-Cl CF₃ C≡C-(2-Cl)Ph H 4 6-Cl CF₃ C≡C-(3-Cl)Ph H 5 6-Cl CF₃ C≡C-(4-Cl)Ph H 6 6-Cl CF₃ C≡C-(2-F)Ph H 7 6-Cl CF₃ C≡C-(3-F)Ph H 8 6-Cl CF₃ C≡C-(4-F)Ph H 9 6-Cl CF₃ C≡C-(2-OH)Ph H 10 6-Cl CF₃ C≡C-(3-OH)Ph H 11 6-Cl CF₃ C≡C-(4-OH)Ph H 12 6-Cl CF₃ C≡C-(2-OMe)Ph H 13 6-Cl CF₃ C≡C-(3-OMe)Ph H 14 6-Cl CF₃ C≡C-(4-OMe)Ph H 15 6-Cl CF₃ C≡C-(2-CN)Ph H 16 6-Cl CF₃ C≡C-(3-CN)Ph H 17 6-Cl CF₃ C≡C-(4-CN)Ph H 18 6-Cl CF₃ C≡C-(2-NO₂)Ph H 19 6-Cl CF₃ C≡C-(3-NO₂)Ph H 20 6-Cl CF₃ C≡C-(4-NO₂)Ph H 21 6-Cl CF₃ C≡C-(2-NH₂)Ph H 22 6-Cl CF₃ C≡C-(3-NH₂)Ph H 23 6-Cl CF₃ C≡C-(4-NH₂)Ph H 24 6-Cl CF₃ C≡C-(2-NMe₂)Ph H 25 6-Cl CF₃ C≡C-(3-NMe₂)Ph H 26 6-Cl CF₃ C≡C-(4-NMe₂)Ph H 27 6-Cl CF₃ C≡C-3-Pyridyl H 28 6-Cl CF₃ C≡C-4-Pyridyl H 29 6-Cl CF₃ C≡C-2-furanyl H 30 6-Cl CF₃ C≡C-3-furanyl H 31 6-Cl CF₃ C≡C-2-thienyl H 32 6-Cl CF₃ C≡C-3-thienyl H 33 6-Cl CF₃ C≡C-2-oxazolyl H 34 6-Cl CF₃ C≡C-2-thiazolyl H 35 6-Cl CF₃ C≡C-4-isoxazolyl H 36 6-Cl CF₃ C≡C-2-imidazolyl H 37 6-Cl CF₃ C═CCH₂CH₂OH H 38 6-Cl CF₃ C═C—CH(OH)Me H 39 6-Cl CF₃ C═C-(2-Cl)Ph H 40 6-Cl CF₃ C═C-(3-Cl)Ph H 41 6-Cl CF₃ C═C-(4-Cl)Ph H 42 6-Cl CF₃ C═C-(2-F)Ph H 43 6-Cl CF₃ C═C-(3-F)Ph H 44 6-Cl CF₃ C═C-(4-F)Ph H 45 6-Cl CF₃ C═C-(2-OH)Ph H 46 6-Cl CF₃ C═C-(3-OH)Ph H 47 6-Cl CF₃ C═C-(4-OH)Ph H 48 6-Cl CF₃ C═C-(2-OMe)Ph H 49 6-Cl CF₃ C═C-(3-OMe)Ph H 50 6-Cl CF₃ C═C-(4-OMe)Ph H 51 6-Cl CF₃ C═C-(2-CN)Ph H 52 6-Cl CF₃ C═C-(3-CN)Ph H 53 6-Cl CF₃ C═C-(4-CN)Ph H 54 6-Cl CF₃ C═C-(2-NO₂)Ph H 55 6-Cl CF₃ C═C-(3-NO₂)Ph H 56 6-Cl CF₃ C═C-(4-NO₂)Ph H 57 6-Cl CF₃ C═C-(2-NH₂)Ph H 58 6-Cl CF₃ C═C-(3-NH₂)Ph H 59 6-Cl CF₃ C═C-(4-NH₂)Ph H 60 6-Cl CF₃ C═C-(2-NMe₂)Ph H 61 6-Cl CF₃ C═C-(3-NMe₂)Ph H 62 6-Cl CF₃ C═C-(4-NMe₂)Ph H 63 6-Cl CF₃ C═C-3-Pyridyl H 64 6-Cl CF₃ C═C-4-Pyridyl H 65 6-Cl CF₃ C═C-2-furanyl H 66 6-Cl CF₃ C═C-3-furanyl H 67 6-Cl CF₃ C═C-2-thienyl H 68 6-Cl CF₃ C═C-3-thienyl H 69 6-Cl CF₃ C═C-2-oxazolyl H 70 6-Cl CF₃ C═C-2-thiazolyl H 71 6-Cl CF₃ C═C-4-isoxazolyl H 72 6-Cl CF₃ C═C-2-imidazolyl H 73 6-Cl CF₃ CH₂CH₂-cycPr H 74 6-Cl CF₃ CH₂CH₂CH₂CH₂OH H 75 6-Cl CF₃ CH₂CH₂—CH(OH)Me H 76 6-Cl CF₃ CH₂CH₂—Ph H 77 6-Cl CF₃ CH₂CH₂-(2-Cl)Ph H 78 6-Cl CF₃ CH₂CH₂-(3-Cl)Ph H 79 6-Cl CF₃ CH₂CH₂-(4-Cl)Ph H 80 6-Cl CF₃ CH₂CH₂-(2-F)Ph H 81 6-Cl CF₃ CH₂CH₂-(3-F)Ph H 82 6-Cl CF₃ CH₂CH₂-(4-F)Ph H 83 6-Cl CF₃ CH₂CH₂-(2-OH)Ph H 84 6-Cl CF₃ CH₂CH₂-(3-OH)Ph H 85 6-Cl CF₃ CH₂CH₂-(4-OH)Ph H 86 6-Cl CF₃ CH₂CH₂-(2-OMe)Ph H 87 6-Cl CF₃ CH₂CH₂-(3-OMe)Ph H 88 6-Cl CF₃ CH₂CH₂-(4-OMe)Ph H 89 6-Cl CF₃ CH₂CH₂-(2-CN)Ph H 90 6-Cl CF₃ CH₂CH₂-(3-CN)Ph H 91 6-Cl CF₃ CH₂CH₂-(4-CN)Ph H 92 6-Cl CF₃ CH₂CH₂-(2-NO₂)Ph H 93 6-Cl CF₃ CH₂CH₂-(3-NO₂)Ph H 94 6-Cl CF₃ CH₂CH₂-(4-NO₂)Ph H 95 6-Cl CF₃ CH₂CH₂-(2-NH₂)Ph H 96 6-Cl CF₃ CH₂CH₂-(3-NH₂)Ph H 97 6-Cl CF₃ CH₂CH₂-(4-NH₂)Ph H 98 6-Cl CF₃ CH₂CH₂-(2-NMe₂)Ph H 99 6-Cl CF₃ CH₂CH₂-(3-NMe₂)Ph H 100 6-Cl CF₃ CH₂CH₂-(4-NMe₂)Ph H 101 6-Cl CF₃ CH₂CH₂-2-Pyridyl H 102 6-Cl CF₃ CH₂CH₂-3-Pyridyl H 103 6-Cl CF₃ CH₂CH₂-4-Pyridyl H 104 6-Cl CF₃ CH₂CH₂-2-furanyl H 105 6-Cl CF₃ CH₂CH₂-3-furanyl H 106 6-Cl CF₃ CH₂CH₂-4-furanyl H 107 6-Cl CF₃ CH₂CH₂-3-thienyl H 108 6-Cl CF₃ CH₂CH₂-2-oxazolyl H 109 6-Cl CF₃ CH₂CH₂-2-thiazolyl H 110 6-Cl CF₃ CH₂CH₂-4-isoxazolyl H 111 6-Cl CF₃ CH₂CH₂-2-imidazolyl H 112 6-Cl CF₃ C≡C-cycPr CH₃ 113 6-Cl CF₃ C≡C—Ph CH₃ 114 6-Cl CF₃ C≡C-2-Pyridyl CH₃ 115 6-Cl CF₃ C≡C-3-Pyridyl CH₃ 116 6-Cl CF₃ C≡C-4-Pyridyl CH₃ 117 6-Cl CF₃ C≡C-2-furanyl CH₃ 118 6-Cl CF₃ C≡C-3-furanyl CH₃ 119 6-Cl CF₃ C≡C-2-thienyl CH₃ 120 6-Cl CF₃ C≡C-3-thienyl CH₃ 121 6-Cl CF₃ C═C-cycPr CH₃ 122 6-Cl CF₃ C═C—Ph CH₃ 123 6-Cl CF₃ C═C-2-Pyridyl CH₃ 124 6-Cl CF₃ C═C-3-Pyridyl CH₃ 125 6-Cl CF₃ C═C-4-Pyridyl CH₃ 126 6-Cl CF₃ C═C-2-furanyl CH₃ 127 6-Cl CF₃ C═C-3-furanyl CH₃ 128 6-Cl CF₃ C═C-2-thienyl CH₃ 129 6-Cl CF₃ C═C-3-thienyl CH₃ 130 6-Cl CF₃ CH₂CH₂-cycPr CH₃ 131 6-Cl CF₃ CH₂CH₂—Ph CH₃ 132 6-Cl CF₃ CH₂CH₂-2-Pyridyl CH₃ 133 6-Cl CF₃ CH₂CH₂-3-Pyridyl CH₃ 134 6-Cl CF₃ CH₂CH₂-4-Pyridyl CH₃ 135 6-Cl CF₃ CH₂CH₂-2-furanyl CH₃ 136 6-Cl CF₃ CH₂CH₂-3-furanyl CH₃ 137 6-Cl CF₃ CH₂CH₂-2-thienyl CH₃ 138 6-Cl CF₃ CH₂CH₂-3-thienyl CH₃ 139 6-Cl CF₃ C≡C-cycPr CH₂CH₃ 140 6-Cl CF₃ C≡C—Ph CH₂CH₃ 141 6-Cl CF₃ C≡C-2-Pyridyl CH₂CH₃ 142 6-Cl CF₃ C≡C-3-Pyridyl CH₂CH₃ 143 6-Cl CF₃ C≡C-4-Pyridyl CH₂CH₃ 144 6-Cl CF₃ C≡C-2-furanyl CH₂CH₃ 145 6-Cl CF₃ C≡C-3-furanyl CH₂CH₃ 146 6-Cl CF₃ C≡C-2-thienyl CH₂CH₃ 147 6-Cl CF₃ C≡C-3-thienyl CH₂CH₃ 148 6-Cl CF₃ C═C-cycPr CH₂CH₃ 149 6-Cl CF₃ C═C—Ph CH₂CH₃ 150 6-Cl CF₃ C═C-2-Pyridyl CH₂CH₃ 151 6-Cl CF₃ C═C-3-Pyridyl CH₂CH₃ 152 6-Cl CF₃ C═C-4-Pyridyl CH₂CH₃ 153 6-Cl CF₃ C═C-2-furanyl CH₂CH₃ 154 6-Cl CF₃ C═C-3-furanyl CH₂CH₃ 155 6-Cl CF₃ C═C-2-thienyl CH₂CH₃ 156 6-Cl CF₃ C═C-3-thienyl CH₂CH₃ 157 6-Cl CF₃ CH₂CH₂-cycPr CH₂CH₃ 158 6-Cl CF₃ CH₂CH₂—Ph CH₂CH₃ 159 6-Cl CF₃ CH₂CH₂-2-Pyridyl CH₂CH₃ 160 6-Cl CF₃ CH₂CH₂-3-Pyridyl CH₂CH₃ 161 6-Cl CF₃ CH₂CH₂-4-Pyridyl CH₂CH₃ 162 6-Cl CF₃ CH₂CH₂-2-furanyl CH₂CH₃ 163 6-Cl CF₃ CH₂CH₂-3-furanyl CH₂CH₃ 164 6-Cl CF₃ CH₂CH₂-2-thienyl CH₂CH₃ 165 6-Cl CF₃ CH₂CH₂-3-thienyl CH₂CH₃ 166 6-MeO CF₃ C≡CCH₂CH₂OH H 167 6-MeO CF₃ C≡C—CH(OH)Me H 168 6-MeO CF₃ C≡C-(2-Cl)Ph H 169 6-MeO CF₃ C≡C-(3-Cl)Ph H 170 6-MeO CF₃ C≡C-(4-Cl)Ph H 171 6-MeO CF₃ C≡C-(2-F)Ph H 172 6-MeO CF₃ C≡C-(3-F)Ph H 173 6-MeO CF₃ C≡C-(4-F)Ph H 174 6-MeO CF₃ C≡C-(2-OH)Ph H 175 6-MeO CF₃ C≡C-(3-OH)Ph H 176 6-MeO CF₃ C≡C-(4-OH)Ph H 177 6-MeO CF₃ C≡C-(2-OMe)Ph H 178 6-MeO CF₃ C≡C-(3-OMe)Ph H 179 6-MeO CF₃ C≡C-(4-OMe)Ph H 180 6-MeO CF₃ C≡C-(2-CN)Ph H 181 6-MeO CF₃ C≡C-(3-CN)Ph H 182 6-MeO CF₃ C≡C-(4-CN)Ph H 183 6-MeO CF₃ C≡C-(2-NO₂)Ph H 184 6-MeO CF₃ C≡C-(3-NO₂)Ph H 185 6-MeO CF₃ C≡C-(4-NO₂)Ph H 186 6-MeO CF₃ C≡C-(2-NH₂)Ph H 187 6-MeO CF₃ C≡C-(3-NH₂)Ph H 188 6-MeO CF₃ C≡C-(4-NH₂)Ph H 189 6-MeO CF₃ C≡C-(2-NMe₂)Ph H 190 6-MeO CF₃ C≡C-(3-NMe₂)Ph H 191 6-MeO CF₃ C≡C-(4-NMe₂)Ph H 192 6-MeO CF₃ C≡C-3-Pyridyl H 193 6-MeO CF₃ C≡C-4-Pyridyl H 194 6-MeO CF₃ C≡C-2-furanyl H 195 6-MeO CF₃ C≡C-3-furanyl H 196 6-MeO CF₃ C≡C-2-thienyl H 197 6-MeO CF₃ C≡C-3-thienyl H 198 6-MeO CF₃ C≡C-2-oxazolyl H 199 6-MeO CF₃ C≡C-2-thiazolyl H 200 6-MeO CF₃ C≡C-4-isoxazolyl H 201 6-MeO CF₃ C≡C-2-imidazolyl H 202 6-MeO CF₃ C═CCH₂CH₂OH H 203 6-MeO CF₃ C═C—CH(OH)Me H 204 6-MeO CF₃ C═C-(2-Cl)Ph H 205 6-MeO CF₃ C═C-(3-Cl)Ph H 206 6-MeO CF₃ C═C-(4-Cl)Ph H 207 6-MeO CF₃ C═C-(2-F)Ph H 208 6-MeO CF₃ C═C-(3-F)Ph H 209 6-MeO CF₃ C═C-(4-F)Ph H 210 6-MeO CF₃ C═C-(2-OH)Ph H 211 6-MeO CF₃ C═C-(3-OH)Ph H 212 6-MeO CF₃ C═C-(4-OH)Ph H 213 6-MeO CF₃ C═C-(2-OMe)Ph H 214 6-MeO CF₃ C═C-(3-OMe)Ph H 215 6-MeO CF₃ C═C-(4-OMe)Ph H 216 6-MeO CF₃ C═C-(2-CN)Ph H 217 6-MeO CF₃ C═C-(3-CN)Ph H 218 6-MeO CF₃ C═C-(4-CN)Ph H 219 6-MeO CF₃ C═C-(2-NO₂)Ph H 220 6-MeO CF₃ C═C-(3-NO₂)Ph H 221 6-MeO CF₃ C═C-(4-NO₂)Ph H 222 6-MeO CF₃ C═C-(2-NH₂)Ph H 223 6-MeO CF₃ C═C-(3-NH₂)Ph H 224 6-MeO CF₃ C═C-(4-NH₂)Ph H 225 6-MeO CF₃ C═C-(2-NMe₂)Ph H 226 6-MeO CF₃ C═C-(3-NMe₂)Ph H 227 6-MeO CF₃ C═C-(4-NMe₂)Ph H 228 6-MeO CF₃ C═C-3-Pyridyl H 229 6-MeO CF₃ C═C-4-Pyridyl H 230 6-MeO CF₃ C═C-2-furanyl H 231 6-MeO CF₃ C═C-3-furanyl H 232 6-MeO CF₃ C═C-2-thienyl H 233 6-MeO CF₃ C═C-3-thienyl H 234 6-MeO CF₃ C═C-2-oxazolyl H 235 6-MeO CF₃ C═C-2-thiazolyl H 236 6-MeO CF₃ C═C-4-isoxazolyl H 237 6-MeO CF₃ C═C-2-imidazolyl H 238 6-MeO CF₃ CH₂CH₂-cycPr H 239 6-MeO CF₃ CH₂CH₂CH₂CH₂OH H 240 6-MeO CF₃ CH₂CH₂—CH(OH)Me H 241 6-MeO CF₃ CH₂CH₂—Ph H 242 6-MeO CF₃ CH₂CH₂-(2-Cl)Ph H 243 6-MeO CF₃ CH₂CH₂-(3-Cl)Ph H 244 6-MeO CF₃ CH₂CH₂-(4-Cl)Ph H 245 6-MeO CF₃ CH₂CH₂-(2-F)Ph H 246 6-MeO CF₃ CH₂CH₂-(3-F)Ph H 247 6-MeO CF₃ CH₂CH₂-(4-F)Ph H 248 6-MeO CF₃ CH₂CH₂-(2-OH)Ph H 249 6-MeO CF₃ CH₂CH₂-(3-OH)Ph H 250 6-MeO CF₃ CH₂CH₂-(4-OH)Ph H 251 6-MeO CF₃ CH₂CH₂-(2-OMe)Ph H 252 6-MeO CF₃ CH₂CH₂-(3-OMe)Ph H 253 6-MeO CF₃ CH₂CH₂-(4-OMe)Ph H 254 6-MeO CF₃ CH₂CH₂-(2-CN)Ph H 255 6-MeO CF₃ CH₂CH₂-(3-CN)Ph H 256 6-MeO CF₃ CH₂CH₂-(4-CN)Ph H 257 6-MeO CF₃ CH₂CH₂-(2-NO₂)Ph H 258 6-MeO CF₃ CH₂CH₂-(3-NO₂)Ph H 259 6-MeO CF₃ CH₂CH₂-(4-NO₂)Ph H 260 6-MeO CF₃ CH₂CH₂-(2-NH₂)Ph H 261 6-MeO CF₃ CH₂CH₂-(3-NH₂)Ph H 262 6-MeO CF₃ CH₂CH₂-(4-NH₂)Ph H 263 6-MeO CF₃ CH₂CH₂-(2-NMe₂)Ph H 264 6-NeO CF₃ CH₂CH₂-(3-NMe₂)Ph H 265 6-MeO CF₃ CH₂CH₂-(4-NMe₂)Ph H 266 6-MeO CF₃ CH₂CH₂-2-Pyridyl H 267 6-MeO CF₃ CH₂CH₂-3-Pyridyl H 268 6-MeO CF₃ CH₂CH₂-4-Pyridyl H 269 6-MeO CF₃ CH₂CH₂-2-furanyl H 270 6-MeO CF₃ CH₂CH₂-3-furanyl H 271 6-MeO CF₃ CH₂CH₂-4-furanyl H 272 6-MeO CF₃ CH₂CH₂-3-thienyl H 273 6-MeO CF₃ CH₂CH₂-2-oxazolyl H 274 6-MeO CF₃ CH₂CH₂-2-thiazolyl H 275 6-MeO CF₃ CH₂CH₂-4-isoxazolyl H 276 6-MeO CF₃ CH₂CH₂-2-imidazolyl H 277 6-MeO CF₃ C≡C-cycPr CH₃ 278 6-MeO CF₃ C≡C—Ph CH₃ 279 6-MeO CF₃ C≡C-2-Pyridyl CH₃ 280 6-MeO CF₃ C≡C-3-Pyridyl CH₃ 281 6-MeO CF₃ C≡C-4-Pyridyl CH₃ 282 6-MeO CF₃ C≡C-2-furanyl CH₃ 283 6-MeO CF₃ C≡C-3-furanyl CH₃ 284 6-MeO CF₃ C≡C-2-thienyl CH₃ 285 6-MeO CF₃ C≡C-3-thienyl CH₃ 286 6-MeO CF₃ C═C-cycPr CH₃ 287 6-MeO CF₃ C═C—Ph CH₃ 288 6-MeO CF₃ C═C-2-Pyridyl CH₃ 289 6-MeO CF₃ C═C-3-Pyridyl CH₃ 290 6-MeO CF₃ C═C-4-Pyridyl CH₃ 291 6-MeO CF₃ C═C-2-furanyl CH₃ 292 6-MeO CF₃ C═C-3-furanyl CH₃ 293 6-MeO CF₃ C═C-2-thienyl CH₃ 294 6-MeO CF₃ C═C-3-thienyl CH₃ 295 6-MeO CF₃ CH₂CH₂-cycPr CH₃ 296 6-MeO CF₃ CH₂CH₂—Ph CH₃ 297 6-MeO CF₃ CH₂CH₂-2-Pyridyl CH₃ 298 6-MeO CF₃ CH₂CH₂-3-Pyridyl CH₃ 299 6-MeO CF₃ CH₂CH₂-4-Pyridyl CH₃ 300 6-MeO CF₃ CH₂CH₂-2-furanyl CH₃ 301 6-MeO CF₃ CH₂CH₂-3-furanyl CH₃ 302 6-MeO CF₃ CH₂CH₂-2-thienyl CH₃ 303 6-MeO CF₃ CH₂CH₂-3-thienyl CH₃ 304 6-MeO CF₃ C≡C-cycPr CH₂CH₃ 305 6-MeO CF₃ C≡C—Ph CH₂CH₃ 306 6-MeO CF₃ C≡C-2-Pyridyl CH₂CH₃ 307 6-MeO CF₃ C≡C-3-Pyridyl CH₂CH₃ 308 6-MeO CF₃ C≡C-4-Pyridyl CH₂CH₃ 309 6-MeO CF₃ C≡C-2-furanyl CH₂CH₃ 310 6-MeO CF₃ C≡C-3-furanyl CH₂CH₃ 311 6-MeO CF₃ C≡C-2-thienyl CH₂CH₃ 312 6-MeO CF₃ C≡C-3-thienyl CH₂CH₃ 313 6-MeO CF₃ C═C-cycPr CH₂CH₃ 314 6-MeO CF₃ C═C—Ph CH₂CH₃ 315 6-MeO CF₃ C═C-2-Pyridyl CH₂CH₃ 316 6-MeO CF₃ C═C-3-Pyridyl CH₂CH₃ 317 6-MeO CF₃ C═C-4-Pyridyl CH₂CH₃ 318 6-MeO CF₃ C═C-2-furanyl CH₂CH₃ 319 6-MeO CF₃ C═C-3-furanyl CH₂CH₃ 320 6-MeO CF₃ C═C-2-thienyl CH₂CH₃ 321 6-MeO CF₃ C═C-3-thienyl CH₂CH₃ 322 6-MeO CF₃ CH₂CH₂-cycPr CH₂CH₃ 323 6-MeO CF₃ CH₂CH₂—Ph CH₂CH₃ 324 6-MeO CF₃ CH₂CH₂-2-Pyridyl CH₂CH₃ 325 6-MeO CF₃ CH₂CH₂-3-Pyridyl CH₂CH₃ 326 6-MeO CF₃ CH₂CH₂-4-Pyridyl CH₂CH₃ 327 6-MeO CF₃ CH₂CH₂-2-furanyl CH₂CH₃ 328 6-MeO CF₃ CH₂CH₂-3-furanyl CH₂CH₃ 329 6-MeO CF₃ CH₂CH₂-2-thienyl CH₂CH₃ 330 6-MeO CF₃ CH₂CH₂-3-thienyl CH₂CH₃ 331 5,6-diF CF₃ C≡C-(2-Cl)Ph H 332 5,6-diF CF₃ C≡C-(3-Cl)Ph H 333 5,6-diF CF₃ C≡C-(4-Cl)Ph H 334 5,6-diF CF₃ C≡C-(2-F)Ph H 335 5,6-diF CF₃ C≡C-(3-F)Ph H 336 5,6-diF CF₃ C≡C-(4-F)Ph H 337 5,6-diF CF₃ C≡C-(2-OH)Ph H 338 5,6-diF CF₃ C≡C-(3-OH)Ph H 339 5,6-diF CF₃ C≡C-(4-OH)Ph H 340 5,6-diF CF₃ C≡C-(2-OMe)Ph H 341 5,6-diF CF₃ C≡C-(3-OMe)Ph H 342 5,6-diF CF₃ C≡C-(4-OMe)Ph H 343 5,6-diF CF₃ C≡C-(2-CN)Ph H 344 5,6-diF CF₃ C≡C-(3-CN)Ph H 345 5,6-diF CF₃ C≡C-(4-CN)Ph H 346 5,6-diF CF₃ C≡C-(2-NO₂)Ph H 347 5,6-diF CF₃ C≡C-(3-NO₂)Ph H 348 5,6-diF CF₃ C≡C-(4-NO₂)Ph H 349 5,6-diF CF₃ C≡C-(2-NH₂)Ph H 350 5,6-diF CF₃ C≡C-(3-NH₂)Ph H 351 5,6-diF CF₃ C≡C-(4-NH₂)Ph H 352 5,6-diF CF₃ C≡C-(2-NMe₂)Ph H 353 5,6-diF CF₃ C≡C-(3-NMe₂)Ph H 354 5,6-diF CF₃ C≡C-(4-NMe₂)Ph H 355 5,6-diF CF₃ C≡C-3-Pyridyl H 356 5,6-diF CF₃ C≡C-4-Pyridyl H 357 5,6-diF CF₃ C≡C-2-furanyl H 358 5,6-diF CF₃ C≡C-3-furanyl H 359 5,6-diF CF₃ C≡C-2-thienyl H 360 5,6-diF CF₃ C≡C-3-thienyl H 361 5,6-diF CF₃ C≡C-2-oxazolyl H 362 5,6-diF CF₃ C≡C-2-thiazolyl H 363 5,6-diF CF₃ C≡C-4-isoxazolyl H 364 5,6-diF CF₃ C≡C-2-imidazolyl H 365 5,6-diF CF₃ C═C-(2-Cl)Ph H 366 5,6-diF CF₃ C═C-(3-Cl)Ph H 367 5,6-diF CF₃ C═C-(4-Cl)Ph H 368 5,6-diF CF₃ C═C-(2-F)Ph H 369 5,6-diF CF₃ C═C-(3-F)Ph H 370 5,6-diF CF₃ C═C-(4-F)Ph H 371 5,6-diF CF₃ C═C-(2-OH)Ph H 372 5,6-diF CF₃ C═C-(3-OH)Ph H 373 5,6-diF CF₃ C═C-(4-OH)Ph H 374 5,6-diF CF₃ C═C-(2-OMe)Ph H 375 5,6-diF CF₃ C═C-(3-OMe)Ph H 376 5,6-diF CF₃ C═C-(4-OMe)Ph H 377 5,6-diF CF₃ C═C-(2-CN)Ph H 378 5,6-diF CF₃ C═C-(3-CN)Ph H 379 5,6-diF CF₃ C═C-(4-CN)Ph H 380 5,6-diF CF₃ C═C-(2-NO₂)Ph H 381 5,6-diF CF₃ C═C-(3-NO₂)Ph H 382 5,6-diF CF₃ C═C-(4-NO₂)Ph H 383 5,6-diF CF₃ C═C-(2-NH₂)Ph H 384 5,6-diF CF₃ C═C-(3-NH₂)Ph H 385 5,6-diF CF₃ C═C-(4-NH₂)Ph H 386 5,6-diF CF₃ C═C-(2-NMe₂)Ph H 387 5,6-diF CF₃ C═C-(3-NMe₂)Ph H 388 5,6-diF CF₃ C═C-(4-NMe₂)Ph H 389 5,6-diF CF₃ C═C-3-Pyridyl H 390 5,6-diF CF₃ C═C-4-Pyridyl H 391 5,6-diF CF₃ C═C-2-furanyl H 392 5,6-diF CF₃ C═C-3-furanyl H 393 5,6-diF CF₃ C═C-2-thienyl H 394 5,6-diF CF₃ C═C-3-thienyl H 395 5,6-diF CF₃ C═C-2-oxazolyl H 396 5,6-diF CF₃ C═C-2-thiazolyl H 397 5,6-diF CF₃ C═C-4-isoxazolyl H 398 5,6-diF CF₃ C═C-2-imidazolyl H 399 5,6-diF CF₃ CH₂CH₂-cycPr H 400 5,6-diF CF₃ CH₂CH₂CH₂CH₂OH H 401 5,6-diF CF₃ CH₂CH₂—CH(OH)Me H 402 5,6-diF CF₃ CH₂CH₂—Ph H 403 5,6-diF CF₃ CH₂CH₂-(2-Cl)Ph H 404 5,6-diF CF₃ CH₂CH₂-(3-Cl)Ph H 405 5,6-diF CF₃ CH₂CH₂-(4-Cl)Ph H 406 5,6-diF CF₃ CH₂CH₂-(2-F)Ph H 407 5,6-diF CF₃ CH₂CH₂-(3-F)Ph H 408 5,6-diF CF₃ CH₂CH₂-(4-F)Ph H 409 5,6-diF CF₃ CH₂CH₂-(2-OH)Ph H 410 5,6-diF CF₃ CH₂CH₂-(3-OH)Ph H 411 5,6-diF CF₃ CH₂CH₂-(4-OH)Ph H 412 5,6-diF CF₃ CH₂CH₂-(2-OMe)Ph H 413 5,6-diF CF₃ CH₂CH₂-(3-OMe)Ph H 414 5,6-diF CF₃ CH₂CH₂-(4-OMe)Ph H 415 5,6-diF CF₃ CH₂CH₂-(2-CN)Ph H 416 5,6-diF CF₃ CH₂CH₂-(3-CN)Ph H 417 5,6-diF CF₃ CH₂CH₂-(4-CN)Ph H 418 5,6-diF CF₃ CH₂CH₂-(2-NO₂)Ph H 419 5,6-diF CF₃ CH₂CH₂-(3-NO₂)Ph H 420 5,6-diF CF₃ CH₂CH₂-(4-NO₂)Ph H 421 5,6-diF CF₃ CH₂CH₂-(2-NH₂)Ph H 422 5,6-diF CF₃ CH₂CH₂-(3-NH₂)Ph H 423 5,6-diF CF₃ CH₂CH₂-(4-NH₂)Ph H 424 5,6-diF CF₃ CH₂CH₂-(2-NMe₂)Ph H 425 5,6-diF CF₃ CH₂CH₂-(3-NMe₂)Ph H 426 5,6-diF CF₃ CH₂CH₂-(4-NMe₂)Ph H 427 5,6-diF CF₃ CH₂CH₂-2-Pyridyl H 428 5,6-diF CF₃ CH₂CH₂-3-Pyridyl H 429 5,6-diF CF₃ CH₂CH₂-4-Pyridyl H 430 5,6-diF CF₃ CH₂CH₂-2-furanyl H 431 5,6-diF CF₃ CH₂CH₂-3-furanyl H 432 5,6-diF CF₃ CH₂CH₂-2-thienyl H 433 5,6-diF CF₃ CH₂CH₂-3-thienyl H 434 5,6-diF CF₃ CH₂CH₂-2-oxazolyl H 435 5,6-diF CF₃ CH₂CH₂-2-thiazolyl H 436 5,6-diF CF₃ CH₂CH₂-4-isoxazolyl H 437 5,6-diF CF₃ CH₂CH₂-2-imidazolyl H 438 5,6-diF CF₃ C≡C-cycPr CH₃ 439 5,6-diF CF₃ C≡C-2-Pyridyl CH₃ 440 5,6-diF CF₃ C≡C-3-Pyridyl CH₃ 441 5,6-diF CF₃ C≡C-4-Pyridyl CH₃ 442 5,6-diF CF₃ C≡C-2-furanyl CH₃ 443 5,6-diF CF₃ C≡C-3-furanyl CH₃ 444 5,6-diF CF₃ C≡C-2-thienyl CH₃ 445 5,6-diF CF₃ C≡C-3-thienyl CH₃ 446 5,6-diF CF₃ C═C-cycPr CH₃ 447 5,6-diF CF₃ C═C-2-Pyridyl CH₃ 448 5,6-diF CF₃ C═C-3-Pyridyl CH₃ 449 5,6-diF CF₃ C═C-4-Pyridyl CH₃ 450 5,6-diF CF₃ C═C-2-furanyl CH₃ 451 5,6-diF CF₃ C═C-3-furanyl CH₃ 452 5,6-diF CF₃ C═C-2-thienyl CH₃ 453 5,6-diF CF₃ C═C-3-thienyl CH₃ 454 5,6-diF CF₃ CH₂CH₂-cycPr CH₃ 455 5,6-diF CF₃ CH₂CH₂—Ph CH₃ 456 5,6-diF CF₃ CH₂CH₂-2-Pyridyl CH₃ 457 5,6-diF CF₃ CH₂CH₂-3-Pyridyl CH₃ 458 5,6-diF CF₃ CH₂CH₂-4-Pyridyl CH₃ 459 5,6-diF CF₃ CH₂CH₂-2-furanyl CH₃ 460 5,6-diF CF₃ CH₂CH₂-3-furanyl CH₃ 461 5,6-diF CF₃ CH₂CH₂-2-thienyl CH₃ 462 5,6-diF CF₃ CH₂CH₂-3-thienyl CH₃ 463 5,6-diF CF₃ C≡C-cycPr CH₂CH₃ 464 5,6-diF CF₃ C≡C—Ph CH₂CH₃ 465 5,6-diF CF₃ C≡C-2-Pyridyl CH₂CH₃ 466 5,6-diF CF₃ C≡C-3-Pyridyl CH₂CH₃ 467 5,6-diF CF₃ C≡C-4-Pyridyl CH₂CH₃ 468 5,6-diF CF₃ C≡C-2-furanyl CH₂CH₃ 469 5,6-diF CF₃ C≡C-3-furanyl CH₂CH₃ 470 5,6-diF CF₃ C≡C-2-thienyl CH₂CH₃ 471 5,6-diF CF₃ C≡C-3-thienyl CH₂CH₃ 472 5,6-diF CF₃ C═C-cycPr CH₂CH₃ 473 5,6-diF CF₃ C═C—Ph CH₂CH₃ 474 5,6-diF CF₃ C═C-2-Pyridyl CH₂CH₃ 475 5,6-diF CF₃ C═C-3-Pyridyl CH₂CH₃ 476 5,6-diF CF₃ C═C-4-Pyridyl CH₂CH₃ 477 5,6-diF CF₃ C═C-2-furanyl CH₂CH₃ 478 5,6-diF CF₃ C═C-3-furanyl CH₂CH₃ 479 5,6-diF CF₃ C═C-2-thienyl CH₂CH₃ 480 5,6-diF CF₃ C═C-3-thienyl CH₂CH₃ 481 5,6-diF CF₃ CH₂CH₂-cycPr CH₂CH₃ 482 5,6-diF CF₃ CH₂CH₂—Ph CH₂CH₃ 483 5,6-diF CF₃ CH₂CH₂-2-Pyridyl CH₂CH₃ 484 5,6-diF CF₃ CH₂CH₂-3-Pyridyl CH₂CH₃ 485 5,6-diF CF₃ CH₂CH₂-4-Pyridyl CH₂CH₃ 486 5,6-diF CF₃ CH₂CH₂-2-furanyl CH₂CH₃ 487 5,6-diF CF₃ CH₂CH₂-3-furanyl CH₂CH₃ 488 5,6-diF CF₃ CH₂CH₂-2-thienyl CH₂CH₃ 489 5,6-diF CF₃ CH₂CH₂-3-thienyl CH₂CH₃ 490 5,6-diCl CF₃ C≡C-(2-Cl)Ph H 491 5,6-diCl CF₃ C≡C-(3-Cl)Ph H 492 5,6-diCl CF₃ C≡C-(4-Cl)Ph H 493 5,6-diCl CF₃ C≡C-(2-F)Ph H 494 5,6-diCl CF₃ C≡C-(3-F)Ph H 495 5,6-diCl CF₃ C≡C-(4-F)Ph H 496 5,6-diCl CF₃ C≡C-(2-OH)Ph H 497 5,6-diCl CF₃ C≡C-(3-OH)Ph H 498 5,6-diCl CF₃ C≡C-(4-OH)Ph H 499 5,6-diCl CF₃ C≡C-(2-OMe)Ph H 500 5,6-diCl CF₃ C≡C-(3-OMe)Ph H 501 5,6-diCl CF₃ C≡C-(4-OMe)Ph H 502 5,6-diCl CF₃ C≡C-(2-CN)Ph H 503 5,6-diCl CF₃ C≡C-(3-CN)Ph H 504 5,6-diCl CF₃ C≡C-(4-CN)Ph H 505 5,6-diCl CF₃ C≡C-(2-NO₂)Ph H 506 5,6-diCl CF₃ C≡C-(3-NO₂)Ph H 507 5,6-diCl CF₃ C≡C-(4-NO₂)Ph H 508 5,6-diCl CF₃ C≡C-(2-NH₂)Ph H 509 5,6-diCl CF₃ C≡C-(3-NH₂)Ph H 510 5,6-diCl CF₃ C≡C-(4-NH₂)Ph H 511 5,6-diCl CF₃ C≡C-(2-NMe₂)Ph H 512 5,6-diCl CF₃ C≡C-(3-NMe₂)Ph H 513 5,6-diCl CF₃ C≡C-(4-NMe₂)Ph H 514 5,6-diCl CF₃ C≡C-3-Pyridyl H 515 5,6-diCl CF₃ C≡C-4-Pyridyl H 516 5,6-diCl CF₃ C≡C-2-furanyl H 517 5,6-diCl CF₃ C≡C-3-furanyl H 518 5,6-diCl CF₃ C≡C-2-thienyl H 519 5,6-diCl CF₃ C≡C-3-thienyl H 520 5,6-diCl CF₃ C≡C-2-oxazolyl H 521 5,6-diCl CF₃ C≡C-2-thiazolyl H 522 5,6-diCl CF₃ C≡C-4-isoxazolyl H 523 5,6-diCl CF₃ C≡C-2-imidazolyl H 524 5,6-diCl CF₃ C═C-(2-Cl)Ph H 525 5,6-diCl CF₃ C═C-(3-Cl)Ph H 526 5,6-diCl CF₃ C═C-(4-Cl)Ph H 527 5,6-diCl CF₃ C═C-(2-F)Ph H 528 5,6-diCl CF₃ C═C-(3-F)Ph H 529 5,6-diCl CF₃ C═C-(4-F)Ph H 530 5,6-diCl CF₃ C═C-(2-OH)Ph H 531 5,6-diCl CF₃ C═C-(3-OH)Ph H 532 5,6-diCl CF₃ C═C-(4-OH)Ph H 533 5,6-diCl CF₃ C═C-(2-OMe)Ph H 534 5,6-diCl CF₃ C═C-(3-OMe)Ph H 535 5,6-diCl CF₃ C═C-(4-OMe)Ph H 536 5,6-diCl CF₃ C═C-(2-CN)Ph H 537 5,6-diCl CF₃ C═C-(3-CN)Ph H 538 5,6-diCl CF₃ C═C-(4-CN)Ph H 539 5,6-diCl CF₃ C═C-(2-NO₂)Ph H 540 5,6-diCl CF₃ C═C-(3-NO₂)Ph H 541 5,6-diCl CF₃ C═C-(4-NO₂)Ph H 542 5,6-diCl CF₃ C═C-(2-NH₂)Ph H 543 5,6-diCl CF₃ C═C-(3-NH₂)Ph H 544 5,6-diCl CF₃ C═C-(4-NH₂)Ph H 545 5,6-diCl CF₃ C═C-(2-NMe₂)Ph H 546 5,6-diCl CF₃ C═C-(3-NMe₂)Ph H 547 5,6-diCl CF₃ C═C-(4-NMe₂)Ph H 548 5,6-diCl CF₃ C═C-3-Pyridyl H 549 5,6-diCl CF₃ C═C-4-Pyridyl H 550 5,6-diCl CF₃ C═C-2-furanyl H 551 5,6-diCl CF₃ C═C-3-furanyl H 552 5,6-diCl CF₃ C═C-2-thienyl H 553 5,6-diCl CF₃ C═C-3-thienyl H 554 5,6-diCl CF₃ C═C-2-oxazolyl H 555 5,6-diCl CF₃ C═C-2-thiazolyl H 556 5,6-diCl CF₃ C═C-4-isoxazolyl H 557 5,6-diCl CF₃ C═C-2-imidazolyl H 558 5,6-diCl CF₃ CH₂CH₂-cycPr H 559 5,6-diCl CF₃ CH₂CH₂CH₂CH₂OH H 560 5,6-diCl CF₃ CH₂CH₂—CH(OH)Me H 561 5,6-diCl CF₃ CH₂CH₂—Ph H 562 5,6-diCl CF₃ CH₂CH₂-(2-Cl)Ph H 563 5,6-diCl CF₃ CH₂CH₂-(3-Cl)Ph H 564 5,6-diCl CF₃ CH₂CH₂-(4-Cl)Ph H 565 5,6-diCl CF₃ CH₂CH₂-(2-F)Ph H 566 5,6-diCl CF₃ CH₂CH₂-(3-F)Ph H 567 5,6-diCl CF₃ CH₂CH₂-(4-F)Ph H 568 5,6-diCl CF₃ CH₂CH₂-(2-OH)Ph H 569 5,6-diCl CF₃ CH₂CH₂-(3-OH)Ph H 570 5,6-diCl CF₃ CH₂CH₂-(4-OH)Ph H 571 5,6-diCl CF₃ CH₂CH₂-(2-OMe)Ph H 572 5,6-diCl CF₃ CH₂CH₂-(3-OMe)Ph H 573 5,6-diCl CF₃ CH₂CH₂-(4-OMe)Ph H 574 5,6-diCl CF₃ CH₂CH₂-(2-CN) Ph H 575 5,6-diCl CF₃ CH₂CH₂-(3-CN)Ph H 576 5,6-diCl CF₃ CH₂CH₂-(4-CN)Ph H 577 5,6-diCl CF₃ CH₂CH₂-(2-NO₂)Ph H 578 5,6-diCl CF₃ CH₂CH₂-(3-NO₂)Ph H 579 5,6-diCl CF₃ CH₂CH₂-(4-NO₂)Ph H 580 5,6-diCl CF₃ CH₂CH₂-(2-NH₂)Ph H 581 5,6-diCl CF₃ CH₂CH₂-(3-NH₂)Ph H 582 5,6-diCl CF₃ CH₂CH₂-(4-NH₂)Ph H 583 5,6-diCl CF₃ CH₂CH₂-(2-NMe₂)Ph H 584 5,6-diCl CF₃ CH₂CH₂-(3-NMe₂)Ph H 585 5,6-diCl CF₃ CH₂CH₂-(4-NMe₂)Ph H 586 5,6-diCl CF₃ CH₂CH₂-2-Pyridyl H 587 5,6-diCl CF₃ CH₂CH₂-3-Pyridyl H 588 5,6-diCl CF₃ CH₂CH₂-4-Pyridyl H 589 5,6-diCl CF₃ CH₂CH₂-2-furanyl H 590 5,6-diCl CF₃ CH₂CH₂-3-furanyl H 591 5,6-diCl CF₃ CH₂CH₂-2-thienyl H 592 5,6-diCl CF₃ CH₂CH₂-3-thienyl H 593 5,6-diCl CF₃ CH₂CH₂-2-oxazolyl H 594 5,6-diCl CF₃ CH₂CH₂-2-thiazolyl H 595 5,6-diCl CF₃ CH₂CH₂-4-isoxazolyl H 596 5,6-diCl CF₃ CH₂CH₂-2-imidazolyl H 597 5,6-diCl CF₃ C≡C-cycPr CH₃ 598 5,6-diCl CF₃ C≡C-2-Pyridyl CH₃ 599 5,6-diCl CF₃ C≡C-3-Pyridyl CH₃ 600 5,6-diCl CF₃ C≡C-4-Pyridyl CH₃ 601 5,6-diCl CF₃ C≡C-2-furanyl CH₃ 602 5,6-diCl CF₃ C≡C-3-furanyl CH₃ 603 5,6-diCl CF₃ C≡C-2-thienyl CH₃ 604 5,6-diCl CF₃ C≡C-3-thienyl CH₃ 605 5,6-diCl CF₃ C═C-cycPr CH₃ 606 5,6-diCl CF₃ C═C-2-Pyridyl CH₃ 607 5,6-diCl CF₃ C═C-3-Pyridyl CH₃ 608 5,6-diCl CF₃ C═C-4-Pyridyl CH₃ 609 5,6-diCl CF₃ C═C-2-furanyl CH₃ 610 5,6-diCl CF₃ C═C-3-furanyl CH₃ 611 5,6-diCl CF₃ C═C-2-thienyl CH₃ 612 5,6-diCl CF₃ C═C-3-thienyl CH₃ 613 5,6-diCl CF₃ CH₂CH₂-cycPr CH₃ 614 5,6-diCl CF₃ CH₂CH₂—Ph CH₃ 615 5,6-diCl CF₃ CH₂CH₂-2-Pyridyl CH₃ 616 5,6-diCl CF₃ CH₂CH₂-3-Pyridyl CH₃ 617 5,6-diCl CF₃ CH₂CH₂-4-Pyridyl CH₃ 618 5,6-diCl CF₃ CH₂CH₂-2-furanyl CH₃ 619 5,6-diCl CF₃ CH₂CH₂-3-furanyl CH₃ 620 5,6-diCl CF₃ CH₂CH₂-2-thienyl CH₃ 621 5,6-diCl CF₃ CH₂CH₂-3-thienyl CH₃ 622 5,6-diCl CF₃ C≡C-cycPr CH₂CH₃ 623 5,6-diCl CF₃ C≡C—Ph CH₂CH₃ 624 5,6-diCl CF₃ C≡C-2-Pyridyl CH₂CH₃ 625 5,6-diCl CF₃ C≡C-3-Pyridyl CH₂CH₃ 626 5,6-diCl CF₃ C≡C-4-Pyridyl CH₂CH₃ 627 5,6-diCl CF₃ C≡C-2-furanyl CH₂CH₃ 628 5,6-diCl CF₃ C≡C-3-furanyl CH₂CH₃ 629 5,6-diCl CF₃ C≡C-2-thienyl CH₂CH₃ 630 5,6-diCl CF₃ C≡C-3-thienyl CH₂CH₃ 631 5,6-diCl CF₃ C═C-cycPr CH₂CH₃ 632 5,6-diCl CF₃ C═C—Ph CH₂CH₃ 633 5,6-diCl CF₃ C═C-2-Pyridyl CH₂CH₃ 634 5,6-diCl CF₃ C═C-3-Pyridyl CH₂CH₃ 635 5,6-diCl CF₃ C═C-4-Pyridyl CH₂CH₃ 636 5,6-diCl CF₃ C═C-2-furanyl CH₂CH₃ 637 5,6-diCl CF₃ C═C-3-furanyl CH₂CH₃ 638 5,6-diCl CF₃ C═C-2-thienyl CH₂CH₃ 639 5,6-diCl CF₃ C═C-3-thienyl CH₂CH₃ 640 5,6-diCl CF₃ CH₂CH₂-cycPr CH₂CH₃ 641 5,6-diCl CF₃ CH₂CH₂—Ph CH₂CH₃ 642 5,6-diCl CF₃ CH₂CH₂-2-Pyridyl CH₂CH₃ 643 5,6-diCl CF₃ CH₂CH₂-3-Pyridyl CH₂CH₃ 644 5,6-diCl CF₃ CH₂CH₂-4-Pyridyl CH₂CH₃ 645 5,6-diCl CF₃ CH₂CH₂-2-furanyl CH₂CH₃ 646 5,6-diCl CF₃ CH₂CH₂-3-furanyl CH₂CH₃ 647 5,6-diCl CF₃ CH₂CH₂-2-thienyl CH₂CH₃ 648 5,6-diCl CF₃ CH₂CH₂-3-thienyl CH₂CH₃ 649 6-F CF₃ C≡CCH₂CH₂OH H 650 6-F CF₃ C≡C—CH(OH)Me H 651 6-F CF₃ C≡C-(2-Cl)Ph H 652 6-F CF₃ C≡C-(3-Cl)Ph H 653 6-F CF₃ C≡C-(4-Cl)Ph H 654 6-F CF₃ C≡C-(2-F)Ph H 655 6-F CF₃ C≡C-(3-F)Ph H 656 6-F CF₃ C≡C-(4-F)Ph H 657 6-F CF₃ C≡C-(2-OH)Ph H 658 6-F CF₃ C≡C-(3-OH)Ph H 659 6-F CF₃ C≡C-(4-OH)Ph H 660 6-F CF₃ C≡C-(2-OMe)Ph H 661 6-F CF₃ C≡C-(3-OMe)Ph H 662 6-F CF₃ C≡C-(4-OMe)Ph H 663 6-F CF₃ C≡C-(2-CN)Ph H 664 6-F CF₃ C≡C-(3-CN)Ph H 665 6-F CF₃ C≡C-(4-CN)Ph H 666 6-F CF₃ C≡C-(2-NO₂)Ph H 667 6-F CF₃ C≡C-(3-NO₂)Ph H 668 6-F CF₃ C≡C-(4-NO₂)Ph H 669 6-F CF₃ C≡C-(2-NH₂)Ph H 670 6-F CF₃ C≡C-(3-NH₂)Ph H 671 6-F CF₃ C≡C-(4-NH₂)Ph H 672 6-F CF₃ C≡C-(2-NMe₂)Ph H 673 6-F CF₃ C≡C-(3-NMe₂)Ph H 674 6-F CF₃ C≡C-(4-NMe₂)Ph H 675 6-F CF₃ C≡C-3-Pyridyl H 676 6-F CF₃ C≡C-4-Pyridyl H 677 6-F CF₃ C≡C-2-furanyl H 678 6-F CF₃ C≡C-3-furanyl H 679 6-F CF₃ C≡C-2-thienyl H 680 6-F CF₃ C≡C-3-thienyl H 681 6-F CF₃ C≡C-2-oxazolyl H 682 6-F CF₃ C≡C-2-thiazolyl H 683 6-F CF₃ C≡C-4-isoxazolyl H 684 6-F CF₃ C≡C-2-imidazolyl H 685 6-F CF₃ C═CCH₂CH₂OH H 686 6-F CF₃ C═C—CH(OH)Me H 687 6-F CF₃ C═C-(2-Cl)Ph H 688 6-F CF₃ C═C-(3-Cl)Ph H 689 6-F CF₃ C═C-(4-Cl)Ph H 690 6-F CF₃ C═C-(2-F)Ph H 691 6-F CF₃ C═C-(3-F)Ph H 692 6-F CF₃ C═C-(4-F)Ph H 693 6-F CF₃ C═C-(2-OH)Ph H 694 6-F CF₃ C═C-(3-OH)Ph H 695 6-F CF₃ C═C-(4-OH)Ph H 696 6-F CF₃ C═C-(2-OMe)Ph H 697 6-F CF₃ C═C-(3-OMe)Ph H 698 6-F CF₃ C═C-(4-OMe)Ph H 699 6-F CF₃ C═C-(2-CN)Ph H 700 6-F CF₃ C═C-(3-CN)Ph H 701 6-F CF₃ C═C-(4-CN)Ph H 702 6-F CF₃ C═C-(2-NO₂)Ph H 703 6-F CF₃ C═C-(3-NO₂)Ph H 704 6-F CF₃ C═C-(4-NO₂)Ph H 705 6-F CF₃ C═C-(2-NH₂)Ph H 706 6-F CF₃ C═C-(3-NH₂)Ph H 707 6-F CF₃ C═C-(4-NH₂)Ph H 708 6-F CF₃ C═C-(2-NMe₂)Ph H 709 6-F CF₃ C═C-(3-NMe₂)Ph H 710 6-F CF₃ C═C-(4-NMe₂)Ph H 711 6-F CF₃ C═C-3-Pyridyl H 712 6-F CF₃ C═C-4-Pyridyl H 713 6-F CF₃ C═C-2-furanyl H 714 6-F CF₃ C═C-3-furanyl H 715 6-F CF₃ C═C-2-thienyl H 716 6-F CF₃ C═C-3-thienyl H 717 6-F CF₃ C═C-2-oxazolyl H 718 6-F CF₃ C═C-2-thiazolyl H 719 6-F CF₃ C═C-4-isoxazolyl H 720 6-F CF₃ C═C-2-imidazolyl H 721 6-F CF₃ CH₂CH₂-cycPr H 722 6-F CF₃ CH₂CH₂CH₂CH₂OH H 723 6-F CF₃ CH₂CH₂—CH(OH)Me H 724 6-F CF₃ CH₂CH₂-(2-Cl)Ph H 725 6-F CF₃ CH₂CH₂-(3-Cl)Ph H 726 6-F CF₃ CH₂CH₂-(4-Cl)Ph H 727 6-F CF₃ CH₂CH₂-(2-F)Ph H 728 6-F CF₃ CH₂CH₂-(3-F)Ph H 729 6-F CF₃ CH₂CH₂-(4-F)Ph H 730 6-F CF₃ CH₂CH₂-(2-OH)Ph H 731 6-F CF₃ CH₂CH₂-(3-OH)Ph H 732 6-F CF₃ CH₂CH₂-(4-OH)Ph H 733 6-F CF₃ CH₂CH₂-(2-OMe)Ph H 734 6-F CF₃ CH₂CH₂-(3-OMe)Ph H 735 6-F CF₃ CH₂CH₂-(4-OMe)Ph H 736 6-F CF₃ CH₂CH₂-(2-CN)Ph H 737 6-F CF₃ CH₂CH₂-(3-CN)Ph H 738 6-F CF₃ CH₂CH₂-(4-CN)Ph H 739 6-F CF₃ CH₂CH₂-(2-NO₂)Ph H 740 6-F CF₃ CH₂CH₂-(3-NO₂)Ph H 741 6-F CF₃ CH₂CH₂-(4-NO₂)Ph H 742 6-F CF₃ CH₂CH₂-(2-NH₂)Ph H 743 6-F CF₃ CH₂CH₂-(3-NH₂)Ph H 744 6-F CF₃ CH₂CH₂-(4-NH₂)Ph H 745 6-F CF₃ CH₂CH₂-(2-NMe₂)Ph H 746 6-F CF₃ CH₂CH₂-(3-NMe₂)Ph H 747 6-F CF₃ CH₂CH₂-(4-NMe₂)Ph H 748 6-F CF₃ CH₂CH₂-3-Pyridyl H 749 6-F CF₃ CH₂CH₂-4-Pyridyl H 750 6-F CF₃ CH₂CH₂-2-furanyl H 751 6-F CF₃ CH₂CH₂-3-furanyl H 752 6-F CF₃ CH₂CH₂-2-thienyl H 753 6-F CF₃ CH₂CH₂-3-thienyl H 754 6-F CF₃ CH₂CH₂-2-oxazolyl H 755 6-F CF₃ CH₂CH₂-2-thiazolyl H 756 6-F CF₃ CH₂CH₂-4-isoxazolyl H 757 6-F CF₃ CH₂CH₂-2-imidazolyl H 758 6-F CF₃ C≡C-cycPr CH₃ 759 6-F CF₃ C≡C-ipr CH₃ 760 6-F CF₃ C≡C—Pr CH₃ 761 6-F CF₃ C≡C—Bu CH₃ 762 6-F CF₃ C≡C-iBu CH₃ 763 6-F CF₃ C≡C-tBu CH₃ 764 6-F CF₃ C≡C—Et CH₃ 765 6-F CF₃ C≡C—Me CH₃ 766 6-F CF₃ C≡C—Ph CH₃ 767 6-F CF₃ C≡C-2-Pyridyl CH₃ 768 6-F CF₃ C≡C-3-Pyridyl CH₃ 769 6-F CF₃ C≡C-4-Pyridyl CH₃ 770 6-F CF₃ C≡C-2-furanyl CH₃ 771 6-F CF₃ C≡C-3-furanyl CH₃ 772 6-F CF₃ C≡C-2-thienyl CH₃ 773 6-F CF₃ C≡C-3-thienyl CH₃ 774 6-F CF₃ C═C-cycPr CH₃ 775 6-F CF₃ C═C-ipr CH₃ 776 6-F CF₃ C═C—Pr CH₃ 777 6-F CF₃ C═C—Bu CH₃ 778 6-F CF₃ C═C-iBu CH₃ 779 6-F CF₃ C═C-tBu CH₃ 780 6-F CF₃ C═C—Et CH₃ 781 6-F CF₃ C═C—Me CH₃ 782 6-F CF₃ C═C—Ph CH₃ 783 6-F CF₃ C═C-2-Pyridyl CH₃ 784 6-F CF₃ C═C-3-Pyridyl CH₃ 785 6-F CF₃ C═C-4-Pyridyl CH₃ 786 6-F CF₃ C═C-2-furanyl CH₃ 787 6-F CF₃ C═C-3-furanyl CH₃ 788 6-F CF₃ C═C-2-thienyl CH₃ 789 6-F CF₃ C═C-3-thienyl CH₃ 790 6-F CF₃ CH₂CH₂-cycPr CH₃ 791 6-F CF₃ CH₂CH₂—Ph CH₃ 792 6-F CF₃ CH₂CH₂-2-Pyridyl CH₃ 793 6-F CF₃ CH₂CH₂-3-Pyridyl CH₃ 794 6-F CF₃ CH₂CH₂-4-Pyridyl CH₃ 795 6-F CF₃ CH₂CH₂-2-furanyl CH₃ 796 6-F CF₃ CH₂CH₂-3-furanyl CH₃ 797 6-F CF₃ CH₂CH₂-2-thienyl CH₃ 798 6-F CF₃ CH₂CH₂-3-thienyl CH₃ 799 6-F CF₃ C≡C-cycPr CH₂CH₃ 800 6-F CF₃ C≡C—Ph CH₂CH₃ 801 6-F CF₃ C≡C-2-Pyridyl CH₂CH₃ 802 6-F CF₃ C≡C-3-Pyridyl CH₂CH₃ 803 6-F CF₃ C≡C-4-Pyridyl CH₂CH₃ 804 6-F CF₃ C≡C-2-furanyl CH₂CH₃ 805 6-F CF₃ C≡C-3-furanyl CH₂CH₃ 806 6-F CF₃ C≡C-2-thienyl CH₂CH₃ 807 6-F CF₃ C≡C-3-thienyl CH₂CH₃ 808 6-F CF₃ C═C-cycPr CH₂CH₃ 809 6-F CF₃ C═C—Ph CH₂CH₃ 810 6-F CF₃ C═C-2-Pyridyl CH₂CH₃ 811 6-F CF₃ C═C-3-Pyridyl CH₂CH₃ 812 6-F CF₃ C═C-4-Pyridyl CH₂CH₃ 813 6-F CF₃ C═C-2-furanyl CH₂CH₃ 814 6-F CF₃ C═C-3-furanyl CH₂CH₃ 815 6-F CF₃ C═C-2-thienyl CH₂CH₃ 816 6-F CF₃ C═C-3-thienyl CH₂CH₃ 817 6-F CF₃ CH₂CH₂-cycPr CH₂CH₃ 818 6-F CF₃ CH₂CH₂—Ph CH₂CH₃ 819 6-F CF₃ CH₂CH₂-2-Pyridyl CH₂CH₃ 820 6-F CF₃ CH₂CH₂-3-Pyridyl CH₂CH₃ 821 6-F CF₃ CH₂CH₂-4-Pyridyl CH₂CH₃ 822 6-F CF₃ CH₂CH₂-2-furanyl CH₂CH₃ 823 6-F CF₃ CH₂CH₂-3-furanyl CH₂CH₃ 824 6-F CF₃ CH₂CH₂-2-thienyl CH₂CH₃ 825 6-F CF₃ CH₂CH₂-3-thienyl CH₂CH₃ 826 5-Cl CF₃ C≡C-cycPr H 827 5-Cl CF₃ C≡CCH₂CH₂OH H 828 5-Cl CF₃ C≡C—CH(OH)Me H 829 5-Cl CF₃ C≡C—Ph H 830 5-Cl CF₃ C≡C-(2-Cl)Ph H 831 5-Cl CF₃ C≡C-(3-Cl)Ph H 832 5-Cl CF₃ C≡C-(4-Cl)Ph H 833 5-Cl CF₃ C≡C-(2-F)Ph H 834 5-Cl CF₃ C≡C-(3-F)Ph H 835 5-Cl CF₃ C≡C-(4-F)Ph H 836 5-Cl CF₃ C≡C-(2-OH)Ph H 837 5-Cl CF₃ C≡C-(3-OH)Ph H 838 5-Cl CF₃ C≡C-(4-OH)Ph H 839 5-Cl CF₃ C≡C-(2-OMe)Ph H 840 5-Cl CF₃ C≡C-(3-OMe)Ph H 841 5-Cl CF₃ C≡C-(4-OMe)Ph H 842 5-Cl CF₃ C≡C-(2-CN)Ph H 843 5-Cl CF₃ C≡C-(3-CN)Ph H 844 5-Cl CF₃ C≡C-(4-CN)Ph H 845 5-Cl CF₃ C≡C-(2-NO₂)Ph H 846 5-Cl CF₃ C≡C-(3-NO₂)Ph H 847 5-Cl CF₃ C≡C-(4-NO₂)Ph H 848 5-Cl CF₃ C≡C-(2-NH₂)Ph H 849 5-Cl CF₃ C≡C-(3-NH₂)Ph H 850 5-Cl CF₃ C≡C-(4-NH₂)Ph H 851 5-Cl CF₃ C≡C-(2-NMe₂)Ph H 852 5-Cl CF₃ C≡C-(3-NMe₂)Ph H 853 5-Cl CF₃ C≡C-(4-NMe₂)Ph H 854 5-Cl CF₃ C≡C-2-Pyridyl H 855 5-Cl CF₃ C≡C-2-Pyridyl H 856 5-Cl CF₃ C≡C-3-Pyridyl H 857 5-Cl CF₃ C≡C-4-Pyridyl H 858 5-Cl CF₃ C≡C-2-furanyl H 859 5-Cl CF₃ C≡C-3-furanyl H 860 5-Cl CF₃ C≡C-2-thienyl H 861 5-Cl CF₃ C≡C-3-thienyl H 862 5-Cl CF₃ C≡C-2-oxazolyl H 863 5-Cl CF₃ C≡C-2-thiazolyl H 864 5-Cl CF₃ C≡C-4-isoxazolyl H 865 5-Cl CF₃ C≡C-2-imidazolyl H 866 5-Cl CF₃ C═C-cycPr H 867 5-Cl CF₃ C═CCH₂CH₂OH H 868 5-Cl CF₃ C═C—CH(OH)Me H 869 5-Cl CF₃ C═C—Ph H 870 5-Cl CF₃ C═C-(2-Cl)Ph H 871 5-Cl CF₃ C═C-(3-Cl)Ph H 872 5-Cl CF₃ C═C-(4-Cl)Ph H 873 5-Cl CF₃ C═C-(2-F)Ph H 874 5-Cl CF₃ C═C-(3-F)Ph H 875 5-Cl CF₃ C═C-(4-F)Ph H 876 5-Cl CF₃ C═C-(2-OH)Ph H 877 5-Cl CF₃ C═C-(3-OH)Ph H 878 5-Cl CF₃ C═C-(4-OH)Ph H 879 5-Cl CF₃ C═C-(2-OMe)Ph H 880 5-Cl CF₃ C═C-(3-OMe)Ph H 881 5-Cl CF₃ C═C-(4-OMe)Ph H 882 5-Cl CF₃ C═C-(2-CN)Ph H 883 5-Cl CF₃ C═C-(3-CN)Ph H 884 5-Cl CF₃ C═C-(4-CN)Ph H 885 5-Cl CF₃ C═C-(2-NO₂)Ph H 886 5-Cl CF₃ C═C-(3-NO₂)Ph H 887 5-Cl CF₃ C═C-(4-NO₂)Ph H 888 5-Cl CF₃ C═C-(2-NH₂)Ph H 889 5-Cl CF₃ C═C-(3-NH₂)Ph H 890 5-Cl CF₃ C═C-(4-NH₂)Ph H 891 5-Cl CF₃ C═C-(2-NMe₂)Ph H 892 5-Cl CF₃ C═C-(3-NMe₂)Ph H 893 5-Cl CF₃ C═C-(4-NMe₂)Ph H 894 5-Cl CF₃ C═C-2-Pyridyl H 895 5-Cl CF₃ C═C-2-Pyridyl H 896 5-Cl CF₃ C═C-3-Pyridyl H 897 5-Cl CF₃ C═C-4-Pyridyl H 898 5-Cl CF₃ C═C-2-furanyl H 899 5-Cl CF₃ C═C-3-furanyl H 900 5-Cl CF₃ C═C-2-thienyl H 901 5-Cl CF₃ C═C-3-thienyl H 902 5-Cl CF₃ C═C-2-oxazolyl H 903 5-Cl CF₃ C═C-2-thiazolyl H 904 5-Cl CF₃ C═C-4-isoxazolyl H 905 5-Cl CF₃ C═C-2-imidazolyl H 906 5-Cl CF₃ CH₂CH₂-cycPr H 907 5-Cl CF₃ CH₂CH₂CH₂CH₂OH H 908 5-Cl CF₃ CH₂CH₂—CH(OH)Me H 909 5-Cl CF₃ CH₂CH₂Ph H 910 5-Cl CF₃ CH₂CH₂-(2-Cl)Ph H 911 5-Cl CF₃ CH₂CH₂-(3-Cl)Ph H 912 5-Cl CF₃ CH₂CH₂-(4-Cl)Ph H 913 5-Cl CF₃ CH₂CH₂-(2-F)Ph H 914 5-Cl CF₃ CH₂CH₂-(3-F)Ph H 915 5-Cl CF₃ CH₂CH₂-(4-F)Ph H 916 5-Cl CF₃ CH₂CH₂-(2-OH)Ph H 917 5-Cl CF₃ CH₂CH₂-(3-OH)Ph H 918 5-Cl CF₃ CH₂CH₂-(4-OH)Ph H 919 5-Cl CF₃ CH₂CH₂-(2-OMe)Ph H 920 5-Cl CF₃ CH₂CH₂-(3-OMe)Ph H 921 5-Cl CF₃ CH₂CH₂-(4-OMe)Ph H 922 5-Cl CF₃ CH₂CH_(2-(2-CN)Ph) H 923 5-Cl CF₃ CH₂CH₂-(3-CN)Ph H 924 5-Cl CF₃ CH₂CH₂-(4-CN)Ph H 925 5-Cl CF₃ CH₂CH₂-(2-NO₂)Ph H 926 5-Cl CF₃ CH₂CH₂-(3-NO₂)Ph H 927 5-Cl CF₃ CH₂CH₂-(4-NO₂)Ph H 928 5-Cl CF₃ CH₂CH₂-(2-NH₂)Ph H 929 5-Cl CF₃ CH₂CH₂-(3-NH₂)Ph H 930 5-Cl CF₃ CH₂CH₂-(4-NH₂)Ph H 931 5-Cl CF₃ CH₂CH₂-(2-NMe₂)Ph H 932 5-Cl CF₃ CH₂CH₂-(3-NMe₂)Ph H 933 5-Cl CF₃ CH₂CH₂-(4-NMe₂)Ph H 934 5-Cl CF₃ CH₂CH₂-2-Pyridyl H 935 5-Cl CF₃ CH₂CH₂-3-Pyridyl H 936 5-Cl CF₃ CH₂CH₂-4-Pyridyl H 937 5-Cl CF₃ CH₂CH₂-2-furanyl H 938 5-Cl CF₃ CH₂CH₂-3-furanyl H 939 5-Cl CF₃ CH₂CH₂-2-thienyl H 940 5-Cl CF₃ CH₂CH₂-3-thienyl H 941 5-Cl CF₃ CH₂CH₂-2-oxazolyl H 942 5-Cl CF₃ CH₂CH₂-2-thiazolyl H 943 5-Cl CF₃ CH₂CH₂-4-isoxazolyl H 944 5-Cl CF₃ CH₂CH₂-2-imidazolyl H 945 5-Cl CF₃ C≡C-cycPr CH₃ 946 5-Cl CF₃ C≡C—Ph CH₃ 947 5-Cl CF₃ C≡C-2-Pyridyl CH₃ 948 5-Cl CF₃ C≡C-3-Pyridyl CH₃ 949 5-Cl CF₃ C≡C-4-Pyridyl CH₃ 950 5-Cl CF₃ C≡C-2-furanyl CH₃ 951 5-Cl CF₃ C≡C-3-furanyl CH₃ 952 5-Cl CF₃ C≡C-2-thienyl CH₃ 953 5-Cl CF₃ C≡C-3-thienyl CH₃ 954 5-Cl CF₃ C═C-cycPr CH₃ 955 5-Cl CF₃ C═C—Ph CH₃ 956 5-Cl CF₃ C═C-2-Pyridyl CH₃ 957 5-Cl CF₃ C═C-3-Pyridyl CH₃ 958 5-Cl CF₃ C═C-4-Pyridyl CH₃ 959 5-Cl CF₃ C═C-2-furanyl CH₃ 960 5-Cl CF₃ C═C-3-furanyl CH₃ 961 5-Cl CF₃ C═C-2-thienyl CH₃ 962 5-Cl CF₃ C═C-3-thienyl CH₃ 963 5-Cl CF₃ CH₂CH₂-cycPr CH₃ 964 5-Cl CF₃ CH₂CH₂—Ph CH₃ 965 5-Cl CF₃ CH₂CH₂-2-Pyridyl CH₃ 966 5-Cl CF₃ CH₂CH₂-3-Pyridyl CH₃ 967 5-Cl CF₃ CH₂CH₂-4-Pyridyl CH₃ 968 5-Cl CF₃ CH₂CH₂-2-furanyl CH₃ 969 5-Cl CF₃ CH₂CH₂-3-furanyl CH₃ 970 5-Cl CF₃ CH₂CH₂-2-thienyl CH₃ 971 5-Cl CF₃ CH₂CH₂-3-thienyl CH₃ 972 5-Cl CF₃ C≡C-cycPr CH₂CH₃ 973 5-Cl CF₃ C≡C—Ph CH₂CH₃ 974 5-Cl CF₃ C≡C-2-Pyridyl CH₂CH₃ 975 5-Cl CF₃ C≡C-3-Pyridyl CH₂CH₃ 976 5-Cl CF₃ C≡C-4-Pyridyl CH₂CH₃ 977 5-Cl CF₃ C≡C-2-furanyl CH₂CH₃ 978 5-Cl CF₃ C≡C-3-furanyl CH₂CH₃ 979 5-Cl CF₃ C≡C-2-thienyl CH₂CH₃ 980 5-Cl CF₃ C≡C-3-thienyl CH₂CH₃ 981 5-Cl CF₃ C═C-cycPr CH₂CH₃ 982 5-Cl CF₃ C═C—Ph CH₂CH₃ 983 5-Cl CF₃ C═C-2-Pyridyl CH₂CH₃ 984 5-Cl CF₃ C═C-3-Pyridyl CH₂CH₃ 985 5-Cl CF₃ C═C-4-Pyridyl CH₂CH₃ 986 5-Cl CF₃ C═C-2-furanyl CH₂CH₃ 987 5-Cl CF₃ C═C-3-furanyl CH₂CH₃ 988 5-Cl CF₃ C═C-2-thienyl CH₂CH₃ 989 5-Cl CF₃ C═C-3-thienyl CH₂CH₃ 990 5-Cl CF₃ CH₂CH₂-cycPr CH₂CH₃ 991 5-Cl CF₃ CH₂CH₂—Ph CH₂CH₃ 992 5-Cl CF₃ CH₂CH₂-2-Pyridyl CH₂CH₃ 993 5-Cl CF₃ CH₂CH₂-3-Pyridyl CH₂CH₃ 994 5-Cl CF₃ CH₂CH₂-4-Pyridyl CH₂CH₃ 995 5-Cl CF₃ CH₂CH₂-2-furanyl CH₂CH₃ 996 5-Cl CF₃ CH₂CH₂-3-furanyl CH₂CH₃ 997 5-Cl CF₃ CH₂CH₂-2-thienyl CH₂CH₃ 998 5-Cl CF₃ CH₂CH₂-3-thienyl CH₂CH₃ 999 5-F CF₃ C≡C-cycPr H 1000 5-F CF₃ C≡CCH₂CH₂OH H 1001 5-F CF₃ C≡C—CH(OH)Me H 1002 5-F CF₃ C≡C—Ph H 1003 5-F CF₃ C≡C-(2-Cl)Ph H 1004 5-F CF₃ C≡C-(3-Cl)Ph H 1005 5-F CF₃ C≡C-(4-Cl)Ph H 1006 5-F CF₃ C≡C-(2-F)Ph H 1007 5-F CF₃ C≡C-(3-F)Ph H 1008 5-F CF₃ C≡C-(4-F)Ph H 1009 5-F CF₃ C≡C-(2-OH)Ph H 1010 5-F CF₃ C≡C-(3-OH)Ph H 1011 5-F CF₃ C≡C-(4-OH)Ph H 1012 5-F CF₃ C≡C-(2-OMe)Ph H 1013 5-F CF₃ C≡C-(3-OMe)Ph H 1014 5-F CF₃ C≡C-(4-OMe)Ph H 1015 5-F CF₃ C≡C-(2-CN)Ph H 1016 5-F CF₃ C≡C-(3-CN)Ph H 1017 5-F CF₃ C≡C-(4-CN)Ph H 1018 5-F CF₃ C≡C-(2-NO₂)Ph H 1019 5-F CF₃ C≡C-(3-NO₂)Ph H 1020 5-F CF₃ C≡C-(4-NO₂)Ph H 1021 5-F CF₃ C≡C-(2-NH₂)Ph H 1022 5-F CF₃ C≡C-(3-NH₂)Ph H 1023 5-F CF₃ C≡C-(4-NH₂)Ph H 1024 5-F CF₃ C≡C-(2-NMe₂)Ph H 1025 5-F CF₃ C≡C-(3-NMe₂)Ph H 1026 5-F CF₃ C≡C-(4-NMe₂)Ph H 1027 5-F CF₃ C≡C-2-Pyridyl H 1028 5-F CF₃ C≡C-2-Pyridyl H 1029 5-F CF₃ C≡C-3-Pyridyl H 1030 5-F CF₃ C≡C-4-Pyridyl H 1031 5-F CF₃ C≡C-2-furanyl H 1032 5-F CF₃ C≡C-3-furanyl H 1033 5-F CF₃ C≡C-2-thienyl H 1034 5-F CF₃ C≡C-3-thienyl H 1035 5-F CF₃ C≡C-2-oxazolyl H 1036 5-F CF₃ C≡C-2-thiazolyl H 1037 5-F CF₃ C≡C-4-isoxazolyl H 1038 5-F CF₃ C≡C-2-imidazolyl H 1039 5-F CF₃ C═C-cycPr H 1040 5-F CF₃ C═CCH₂CH₂OH H 1041 5-F CF₃ C═C—CH(OH)Me H 1042 5-F CF₃ C═C—Ph H 1043 5-F CF₃ C═C-(2-Cl)Ph H 1044 5-F CF₃ C═C-(3-Cl)Ph H 1045 5-F CF₃ C═C-(4-Cl)Ph H 1046 5-F CF₃ C═C-(2-F)Ph H 1047 5-F CF₃ C═C-(3-F)Ph H 1048 5-F CF₃ C═C-(4-F)Ph H 1049 5-F CF₃ C═C-(2-OH)Ph H 1050 5-F CF₃ C═C-(3-OH)Ph H 1051 5-F CF₃ C═C-(4-OH)Ph H 1052 5-F CF₃ C═C-(2-OMe)Ph H 1053 5-F CF₃ C═C-(3-OMe)Ph H 1054 5-F CF₃ C═C-(4-OMe)Ph H 1055 5-F CF₃ C═C-(2-CN)Ph H 1056 5-F CF₃ C═C-(3-CN)Ph H 1057 5-F CF₃ C═C-(4-CN)Ph H 1058 5-F CF₃ C═C-(2-NO₂)Ph H 1059 5-F CF₃ C═C-(3-NO₂)Ph H 1060 5-F CF₃ C═C-(4-NO₂)Ph H 1061 5-F CF₃ C═C-(2-NH₂)Ph H 1062 5-F CF₃ C═C-(3-NH₂)Ph H 1063 5-F CF₃ C═C-(4-NH₂)Ph H 1064 5-F CF₃ C═C-(2-NMe₂)Ph H 1065 5-F CF₃ C═C-(3-NMe₂)Ph H 1066 5-F CF₃ C═C-(4-NMe₂)Ph H 1067 5-F CF₃ C═C-2-Pyridyl H 1068 5-F CF₃ C═C-2-Pyridyl H 1069 5-F CF₃ C═C-3-Pyridyl H 1070 5-F CF₃ C═C-4-Pyridyl H 1071 5-F CF₃ C═C-2-furanyl H 1072 5-F CF₃ C═C-3-furanyl H 1073 5-F CF₃ C═C-2-thienyl H 1074 5-F CF₃ C═C-3-thienyl H 1075 5-F CF₃ C═C-2-oxazolyl H 1076 5-F CF₃ C═C-2-thiazolyl H 1077 5-F CF₃ C═C-4-isoxazolyl H 1078 5-F CF₃ C═C-2-imidazolyl H 1079 5-F CF₃ CH₂CH₂-cycPr H 1080 S-F CF₃ CH₂CH₂CH₂CH₂OH H 1081 5-F CF₃ CH₂CH₂—CH(OH)Me H 1082 5-F CF₃ CH₂CH₂Ph H 1083 5-F CF₃ CH₂CH₂-(2-Cl)Ph H 1084 5-F CF₃ CH₂CH₂-(3-Cl)Ph H 1085 5-F CF₃ CH₂CH₂-(4-Cl)Ph H 1086 5-F CF₃ CH₂CH₂-(2-F)Ph H 1087 5-F CF₃ CH₂CH₂-(3-F)Ph H 1088 5-F CF₃ CH₂CH₂-(4-F)Ph H 1089 5-F CF₃ CH₂CH₂-(2-OH)Ph H 1090 5-F CF₃ CH₂CH₂-(3-OH)Ph H 1091 5-F CF₃ CH₂CH₂-(4-OH)Ph H 1092 5-F CF₃ CH₂CH₂-(2-OMe)Ph H 1093 5-F CF₃ CH₂CH₂-(3-OMe)Ph H 1094 5-F CF₃ CH₂CH₂-(4-OMe)Ph H 1095 5-F CF₃ CH₂CH₂-(2-CN)Ph H 1096 5-F CF₃ CH₂CH₂-(3-CN)Ph H 1097 5-F CF₃ CH₂CH₂-(4-CN)Ph H 1098 5-F CF₃ CH₂CH₂-(2-NO₂)Ph H 1099 5-F CF₃ CH₂CH₂-(3-NO₂)Ph H 1100 5-F CF₃ CH₂CH₂-(4-NO₂)Ph H 1101 5-F CF₃ CH₂CH₂-(2-NH₂)Ph H 1102 5-F CF₃ CH₂CH₂-(3-NH₂)Ph H 1103 5-F CF₃ CH₂CH₂-(4-NH₂)Ph H 1104 5-F CF₃ CH₂CH₂-(2-NMe₂)Ph H 1105 5-F CF₃ CH₂CH₂-(3-NMe₂)Ph H 1106 5-F CF₃ CH₂CH₂-(4-NMe₂)Ph H 1107 5-F CF₃ CH₂CH₂-2-Pyridyl H 1108 5-F CF₃ CH₂CH₂-3-Pyridyl H 1109 5-F CF₃ CH₂CH₂-4-Pyridyl H 1110 5-F CF₃ CH₂CH₂-2-furanyl H 1111 5-F CF₃ CH₂CH₂-3-furanyl H 1112 5-F CF₃ CH₂CH₂-2-thienyl H 1113 5-F CF₃ CH₂CH₂-3-thienyl H 1114 5-F CF₃ CH₂CH₂-2-oxazolyl H 1115 5-F CF₃ CH₂CH₂-2-thiazolyl H 1116 5-F CF₃ CH₂CH₂-4-isoxazolyl H 1117 5-F CF₃ CH₂CH₂-2-imidazolyl H 1118 5-F CF₃ C≡C-cycPr CH₃ 1119 5-F CF₃ C≡C—Ph CH₃ 1120 5-F CF₃ C≡C-2-Pyridyl CH₃ 1121 5-F CF₃ C≡C-3-Pyridyl CH₃ 1122 5-F CF₃ C≡C-4-Pyridyl CH₃ 1123 5-F CF₃ C≡C-2-furanyl CH₃ 1124 5-F CF₃ C≡C-3-furanyl CH₃ 1125 5-F CF₃ C≡C-2-thienyl CH₃ 1126 5-F CF₃ C≡C-3-thienyl CH₃ 1127 5-F CF₃ C═C-cycPr CH₃ 1128 5-F CF₃ C═C—Ph CH₃ 1129 5-F CF₃ C═C-2-Pyridyl CH₃ 1130 5-F CF₃ C═C-3-Pyridyl CH₃ 1131 5-F CF₃ C═C-4-Pyridyl CH₃ 1132 5-F CF₃ C═C-2-furanyl CH₃ 1133 5-F CF₃ C═C-3-furanyl CH₃ 1134 5-F CF₃ C═C-2-thienyl CH₃ 1135 5-F CF₃ C═C-3-thienyl CH₃ 1136 5-F CF₃ CH₂CH₂-cycPr CH₃ 1137 5-F CF₃ CH₂CH₂—Ph CH₃ 1138 5-F CF₃ CH₂CH₂-2-Pyridyl CH₃ 1139 5-F CF₃ CH₂CH₂-3-Pyridyl CH₃ 1140 5-F CF₃ CH₂CH₂-4-Pyridyl CH₃ 1141 5-F CF₃ CH₂CH₂-2-furanyl CH₃ 1142 5-F CF₃ CH₂CH₂-3-furanyl CH₃ 1143 5-F CF₃ CH₂CH₂-2-thienyl CH₃ 1144 5-F CF₃ CH₂CH₂-3-thienyl CH₃ 1145 5-F CF₃ C≡C-cycPr CH₂CH₃ 1146 5-F CF₃ C≡C—Ph CH₂CH₃ 1147 5-F CF₃ C≡C-2-Pyridyl CH₂CH₃ 1148 5-F CF₃ C≡C-3-Pyridyl CH₂CH₃ 1149 5-F CF₃ C≡C-4-Pyridyl CH₂CH₃ 1150 5-F CF₃ C≡C-2-furanyl CH₂CH₃ 1151 5-F CF₃ C≡C-3-furanyl CH₂CH₃ 1152 5-F CF₃ C≡C-2-thienyl CH₂CH₃ 1153 5-F CF₃ C≡C-3-thienyl CH₂CH₃ 1154 5-F CF₃ C═C-cycPr CH₂CH₃ 1155 5-F CF₃ C═C—Ph CH₂CH₃ 1156 5-F CF₃ C═C-2-Pyridyl CH₂CH₃ 1157 5-F CF₃ C═C-3-Pyridyl CH₂CH₃ 1158 5-F CF₃ C═C-4-Pyridyl CH₂CH₃ 1159 S-F CF₃ C═C-2-furanyl CH₂CH₃ 1160 5-F CF₃ C═C-3-furanyl CH₂CH₃ 1161 5-F CF₃ C═C-2-thienyl CH₂CH₃ 1162 5-F CF₃ C═C-3-thienyl CH₂CH₃ 1163 5-F CF₃ CH₂CH₂-cycPr CH₂CH₃ 1164 5-F CF₃ CH₂CH₂—Ph CH₂CH₃ 1165 5-F CF₃ CH₂CH₂-2-Pyridyl CH₂CH₃ 1166 5-F CF₃ CH₂CH₂-3-Pyridyl CH₂CH₃ 1167 5-F CF₃ CH₂CH₂-4-Pyridyl CH₂CH₃ 1168 5-F CF₃ CH₂CH₂-2-furanyl CH₂CH₃ 1169 5-F CF₃ CH₂CH₂-3-furanyl CH₂CH₃ 1170 5-F CF₃ CH₂CH₂-2-thienyl CH₂CH₃ 1171 5-F CF₃ CH₂CH₂-3-thienyl CH₂CH₃ 1172 5-Cl, 6-F CF₃ C≡C-cycPr H 1173 5-Cl, 6-F CF₃ C≡C—Ph H 1174 5-Cl, 6-F CF₃ C≡C-2-Pyridyl H 1175 5-Cl, 6-F CF₃ C≡C-3-Pyridyl H 1176 5-Cl, 6-F CF₃ C≡C-4-Pyridyl H 1177 5-Cl, 6-F CF₃ C≡C-2-furanyl H 1178 5-Cl, 6-F CF₃ C≡C-3-furanyl H 1179 5-Cl, 6-F CF₃ C≡C-2-thienyl H 1180 5-Cl, 6-F CF₃ C≡C-3-thienyl H 1181 5-Cl, 6-F CF₃ C═C-cycPr H 1182 5-Cl, 6-F CF₃ C═C—Ph H 1183 5-Cl, 6-F CF₃ C═C-2-Pyridyl H 1184 5-Cl, 6-F CF₃ C═C-3-Pyridyl H 1185 5-Cl, 6-F CF₃ C═C-4-Pyridyl H 1186 5-Cl, 6-F CF₃ C═C-2-furanyl H 1187 5-Cl, 6-F CF₃ C═C-3-furanyl H 1188 5-Cl, 6-F CF₃ C═C-2-thienyl H 1189 5-Cl, 6-F CF₃ C═C-3-thienyl H 1190 5-Cl, 6-F CF₃ CH₂CH₂-cycPr H 1191 5-Cl, 6-F CF₃ CH₂CH₂—Ph H 1192 5-Cl, 6-F CF₃ CH₂CH₂-2-Pyridyl H 1193 5-Cl, 6-F CF₃ CH₂CH₂-3-Pyridyl H 1194 5-Cl, 6-F CF₃ CH₂CH₂-4-Pyridyl H 1195 5-Cl, 6-F CF₃ CH₂CH₂-2-furanyl H 1196 5-Cl, 6-F CF₃ CH₂CH₂-3-furanyl H 1197 5-Cl, 6-F CF₃ CH₂CH₂-2-thienyl H 1198 5-Cl, 6-F CF₃ CH₂CH₂-3-thienyl H 1199 5-Cl, 6-F CF₃ C≡C-cycPr CH₃ 1200 5-Cl, 6-F CF₃ C≡C—Ph CH₃ 1201 5-Cl, 6-F CF₃ C≡C-2-Pyridyl CH₃ 1202 5-Cl, 6-F CF₃ C≡C-3-Pyridyl CH₃ 1203 5-Cl, 6-F CF₃ C≡C-4-Pyridyl CH₃ 1204 5-Cl, 6-F CF₃ C≡C-2-furanyl CH₃ 1205 5-Cl, 6-F CF₃ C≡C-3-furanyl CH₃ 1206 5-Cl, 6-F CF₃ C≡C-2-thienyl CH₃ 1207 5-Cl, 6-F CF₃ C≡C-3-thienyl CH₃ 1208 5-Cl, 6-F CF₃ C═C-cycPr CH₃ 1209 5-Cl, 6-F CF₃ C═C—Ph CH₃ 1210 5-Cl, 6-F CF₃ C═C-2-Pyridyl CH₃ 1211 5-Cl, 6-F CF₃ C═C-3-Pyridyl CH₃ 1212 5-Cl, 6-F CF₃ C═C-4-Pyridyl CH₃ 1213 5-Cl, 6-F CF₃ C═C-2-furanyl CH₃ 1214 5-Cl, 6-F CF₃ C═C-3-furanyl CH₃ 1215 5-Cl, 6-F CF₃ C═C-2-thienyl CH₃ 1216 5-Cl, 6-F CF₃ C═C-3-thienyl CH₃ 1217 5-Cl, 6-F CF₃ CH₂CH₂-cycPr CH₃ 1218 5-Cl, 6-F CF₃ CH₂CH₂—Ph CH₃ 1219 5-Cl, 6-F CF₃ CH₂CH₂-2-Pyridyl CH₃ 1220 5-Cl, 6-F CF₃ CH₂CH₂-3-Pyridyl CH₃ 1221 5-Cl, 6-F CF₃ CH₂CH₂-4-Pyridyl CH₃ 1222 5-Cl, 6-F CF₃ CH₂CH₂-2-furanyl CH₃ 1223 5-Cl, 6-F CF₃ CH₂CH₂-3-furanyl CH₃ 1224 5-Cl, 6-F CF₃ CH₂CH₂-2-thienyl CH₃ 1225 5-Cl, 6-F CF₃ CH₂CH₂-3-thienyl CH₃ 1226 5-F, 6-Cl CF₃ C≡C-cycPr H 1227 5-F, 6-Cl CF₃ C≡C—Ph H 1228 5-F, 6-Cl CF₃ C≡C-2-Pyridyl H 1229 5-F, 6-Cl CF₃ C≡C-3-Pyridyl H 1230 5-F, 6-Cl CF₃ C≡C-4-Pyridyl H 1231 5-F, 6-Cl CF₃ C≡C-2-furanyl H 1232 5-F, 6-Cl CF₃ C≡C-3-furanyl H 1233 5-F, 6-Cl CF₃ C≡C-2-thienyl H 1234 5-F, 6-Cl CF₃ C≡C-3-thienyl H 1235 5-F, 6-Cl CF₃ C═C-cycPr H 1236 5-F, 6-Cl CF₃ C═C—Ph H 1237 5-F, 6-Cl CF₃ C═C-2-Pyridyl H 1238 5-F, 6-Cl CF₃ C═C-3-Pyridyl H 1239 5-F, 6-Cl CF₃ C═C-4-Pyridyl H 1240 5-F, 6-Cl CF₃ C═C-2-furanyl H 1241 5-F, 6-Cl CF₃ C═C-3-furanyl H 1242 5-F, 6-Cl CF₃ C═C-2-thienyl H 1243 5-F, 6-Cl CF₃ C═C-3-thienyl H 1244 5-F, 6-Cl CF₃ CH₂CH₂-cycPr H 1245 5-F, 6-Cl CF₃ CH₂CH₂—Ph H 1246 5-F, 6-Cl CF₃ CH₂CH₂-2-Pyridyl H 1247 5-F, 6-Cl CF₃ CH₂CH₂-3-Pyridyl H 1248 5-F, 6-Cl CF₃ CH₂CH₂-4-Pyridyl H 1249 5-F, 6-Cl CF₃ CH₂CH₂-2-furanyl H 1250 5-F, 6-Cl CF₃ CH₂CH₂-3-furanyl H 1251 5-F, 6-Cl CF₃ CH₂CH₂-2-thienyl H 1252 5-F, 6-Cl CF₃ CH₂CH₂-3-thienyl H 1253 5-F, 6-Cl CF₃ C≡C-cycPr CH₃ 1254 5-F, 6-Cl CF₃ C≡C—Ph CH₃ 1255 5-F, 6-Cl CF₃ C≡C-2-Pyridyl CH₃ 1256 5-F, 6-Cl CF₃ C≡C-3-Pyridyl CH₃ 1257 5-F, 6-Cl CF₃ C≡C-4-Pyridyl CH₃ 1258 5-F, 6-Cl CF₃ C≡C-2-furanyl CH₃ 1259 5-F, 6-Cl CF₃ C≡C-3-furanyl CH₃ 1260 5-F, 6-Cl CF₃ C≡C-2-thienyl CH₃ 1261 5-F, 6-Cl CF₃ C≡C-3-thienyl CH₃ 1262 5-F, 6-Cl CF₃ C═C-cycPr CH₃ 1263 5-F, 6-Cl CF₃ C═C—Ph CH₃ 1264 5-F, 6-Cl CF₃ C═C-2-Pyridyl CH₃ 1265 5-F, 6-Cl CF₃ C═C-3-Pyridyl CH₃ 1266 5-F, 6-Cl CF₃ C═C-4-Pyridyl CH₃ 1267 5-F, 6-Cl CF₃ C═C-2-furanyl CH₃ 1268 5-F, 6-Cl CF₃ C═C-3-furanyl CH₃ 1269 5-F, 6-Cl CF₃ C═C-2-thienyl CH₃ 1270 5-F, 6-Cl CF₃ C═C-3-thienyl CH₃ 1271 5-F, 6-Cl CF₃ CH₂CH₂-cycPr CH₃ 1272 5-F, 6-Cl CF₃ CH₂CH₂—Ph CH₃ 1273 5-F, 6-Cl CF₃ CH₂CH₂-2-Pyridyl CH₃ 1274 5-F, 6-Cl CF₃ CH₂CH₂-3-Pyridyl CH₃ 1275 5-F, 6-Cl CF₃ CH₂CH₂-4-Pyridyl CH₃ 1276 5-F, 6-Cl CF₃ CH₂CH₂-2-furanyl CH₃ 1277 5-F, 6-Cl CF₃ CH₂CH₂-3-furanyl CH₃ 1278 5-F, 6-Cl CF₃ CH₂CH₂-2-thienyl CH₃ 1279 5-F, 6-Cl CF₃ CH₂CH₂-3-thienyl CH₃ 1280 6-Cl, 8-F CF₃ C≡C-cycPr H 1281 6-Cl, 8-F CF₃ C≡C—Ph H 1282 6-Cl, 8-F CF₃ C≡C-2-Pyridyl H 1283 6-Cl, 8-F CF₃ C≡C-3-Pyridyl H 1284 6-Cl, 8-F CF₃ C≡C-4-Pyridyl H 1285 6-Cl, 8-F CF₃ C≡C-2-furanyl H 1286 6-Cl, 8-F CF₃ C≡C-3-furanyl H 1287 6-Cl, 8-F CF₃ C≡C-2-thienyl H 1288 6-Cl, 8-F CF₃ C≡C-3-thienyl H 1289 6-Cl, 8-F CF₃ C═C-cycPr H 1290 6-Cl, 8-F CF₃ C═C—Ph H 1291 6-Cl, 8-F CF₃ C═C-2-Pyridyl H 1292 6-Cl, 8-F CF₃ C═C-3-Pyridyl H 1293 6-Cl, 8-F CF₃ C═C-4-Pyridyl H 1294 6-Cl, 8-F CF₃ C═C-2-furanyl H 1295 6-Cl, 8-F CF₃ C═C-3-furanyl H 1296 6-Cl, 8-F CF₃ C═C-2-thienyl H 1297 6-Cl, 8-F CF₃ C═C-3-thienyl H 1298 6-Cl, 8-F CF₃ CH₂CH₂-cycPr H 1299 6-Cl, 8-F CF₃ CH₂CH₂—Ph H 1300 6-Cl, 8-F CF₃ CH₂CH₂-2-Pyridyl H 1301 6-Cl, 8-F CF₃ CH₂CH₂-3-Pyridyl H 1302 6-Cl, 8-F CF₃ CH₂CH₂-4-Pyridyl H 1303 6-Cl, 8-F CF₃ CH₂CH₂-2-furanyl H 1304 6-Cl, 8-F CF₃ CH₂CH₂-3-furanyl H 1305 6-Cl, 8-F CF₃ CH₂CH₂-2-thienyl H 1306 6-Cl, 8-F CF₃ CH₂CH₂-3-thienyl H 1307 6-Cl, 8-F CF₃ C≡C-cycPr CH₃ 1308 6-Cl, 8-F CF₃ C≡C—Ph CH₃ 1309 6-Cl, 8-F CF₃ C≡C-2-Pyridyl CH₃ 1310 6-Cl, 8-F CF₃ C≡C-3-Pyridyl CH₃ 1311 6-Cl, 8-F CF₃ C≡C-4-Pyridyl CH₃ 1312 6-Cl, 8-F CF₃ C≡C-2-furanyl CH₃ 1313 6-Cl, 8-F CF₃ C≡C-3-furanyl CH₃ 1314 6-Cl, 8-F CF₃ C≡C-2-thienyl CH₃ 1315 6-Cl, 8-F CF₃ C≡C-3-thienyl CH₃ 1316 6-Cl, 8-F CF₃ C═C-cycPr CH₃ 1317 6-Cl, 8-F CF₃ C═C—Ph CH₃ 1318 6-Cl, 8-F CF₃ C═C-2-Pyridyl CH₃ 1319 6-Cl, 8-F CF₃ C═C-3-Pyridyl CH₃ 1320 6-Cl, 8-F CF₃ C═C-4-Pyridyl CH₃ 1321 6-Cl, 8-F CF₃ C═C-2-furanyl CH₃ 1322 6-Cl, 8-F CF₃ C═C-3-furanyl CH₃ 1323 6-Cl, 8-F CF₃ C═C-2-thienyl CH₃ 1324 6-Cl, 8-F CF₃ C═C-3-thienyl CH₃ 1325 6-Cl, 8-F CF₃ CH₂CH₂-cycPr CH₃ 1326 6-Cl, 8-F CF₃ CH₂CH₂—Ph CH₃ 1327 6-Cl, 8-F CF₃ CH₂CH₂-2-Pyridyl CH₃ 1328 6-Cl, 8-F CF₃ CH₂CH₂-3-Pyridyl CH₃ 1329 6-Cl, 8-F CF₃ CH₂CH₂-4-Pyridyl CH₃ 1330 6-Cl, 8-F CF₃ CH₂CH₂-2-furanyl CH₃ 1331 6-Cl, 8-F CF₃ CH₂CH₂-3-furanyl CH₃ 1332 6-Cl, 8-F CF₃ CH₂CH₂-2-thienyl CH₃ 1333 6-Cl, 8-F CF₃ CH₂CH₂-3-thienyl CH₃ 1334 6-CH₃ CF₃ C≡C-cycPr H 1335 6-CH₃ CF₃ C≡C—Ph H 1336 6-CH₃ CF₃ C≡C-2-Pyridyl H 1337 6-CH₃ CF₃ C≡C-3-Pyridyl H 1338 6-CH₃ CF₃ C≡C-4-Pyridyl H 1339 6-CH₃ CF₃ C≡C-2-furanyl H 1340 6-CH₃ CF₃ C≡C-3-furanyl H 1341 6-CH₃ CF₃ C≡C-2-thienyl H 1342 6-CH₃ CF₃ C≡C-3-thienyl H 1343 6-CH₃ CF₃ C═C-cycPr H 1344 6-CH₃ CF₃ C═C—Ph H 1345 6-CH₃ CF₃ C═C-2-Pyridyl H 1346 6-CH₃ CF₃ C═C-3-Pyridyl H 1347 6-CH₃ CF₃ C═C-4-Pyridyl H 1348 6-CH₃ CF₃ C═C-2-furanyl H 1349 6-CH₃ CF₃ C═C-3-furanyl H 1350 6-CH₃ CF₃ C═C-2-thienyl H 1351 6-CH₃ CF₃ C═C-3-thienyl H 1352 6-CH₃ CF₃ CH₂CH₂-cycPr H 1353 6-CH₃ CF₃ CH₂CH₂—Ph H 1354 6-CH₃ CF₃ CH₂CH₂-2-Pyridyl H 1355 6-CH₃ CF₃ CH₂CH₂-3-Pyridyl H 1356 6-CH₃ CF₃ CH₂CH₂-4-Pyridyl H 1357 6-CH₃ CF₃ CH₂CH₂-2-furanyl H 1358 6-CH₃ CF₃ CH₂CH₂-3-furanyl H 1359 6-CH₃ CF₃ CH₂CH₂-2-thienyl H 1360 6-CH₃ CF₃ CH₂CH₂-3-thienyl H 1361 6-CH₃ CF₃ C≡C-cycPr CH₃ 1362 6-CH₃ CF₃ C≡C—Ph CH₃ 1363 6-CH₃ CF₃ C≡C-2-Pyridyl CH₃ 1364 6-CH₃ CF₃ C≡C-3-Pyridyl CH₃ 1365 6-CH₃ CF₃ C≡C-4-Pyridyl CH₃ 1366 6-CH₃ CF₃ C≡C-2-furanyl CH₃ 1367 6-CH₃ CF₃ C≡C-3-furanyl CH₃ 1368 6-CH₃ CF₃ C≡C-2-thienyl CH₃ 1369 6-CH₃ CF₃ C≡C-3-thienyl CH₃ 1370 6-CH₃ CF₃ C═C-cycPr CH₃ 1371 6-CH₃ CF₃ C═C—Ph CH₃ 1372 6-CH₃ CF₃ C═C-2-Pyridyl CH₃ 1373 6-CH₃ CF₃ C═C-3-Pyridyl CH₃ 1374 6-CH₃ CF₃ C═C-4-Pyridyl CH₃ 1375 6-CH₃ CF₃ C═C-2-furanyl CH₃ 1376 6-CH₃ CF₃ C═C-3-furanyl CH₃ 1377 6-CH₃ CF₃ C═C-2-thienyl CH₃ 1378 6-CH₃ CF₃ C═C-3-thienyl CH₃ 1379 6-CH₃ CF₃ CH₂CH₂-cycPr CH₃ 1380 6-CH₃ CF₃ CH₂CH₂—Ph CH₃ 1381 6-CH₃ CF₃ CH₂CH₂-2-Pyridyl CH₃ 1382 6-CH₃ CF₃ CH₂CH₂-3-Pyridyl CH₃ 1383 6-CH₃ CF₃ CH₂CH₂-4-Pyridyl CH₃ 1384 6-CH₃ CF₃ CH₂CH₂-2-furanyl CH₃ 1385 6-CH₃ CF₃ CH₂CH₂-3-furanyl CH₃ 1386 6-CH₃ CF₃ CH₂CH₂-2-thienyl CH₃ 1387 6-CH₃ CF₃ CH₂CH₂-3-thienyl CH₃ 1388 6-COCH₃ CF₃ C≡C-cycPr H 1389 6-COCH₃ CF₃ C≡C—Ph H 1390 6-COCH₃ CF₃ C≡C-2-Pyridyl H 1391 6-COCH₃ CF₃ C≡C-3-Pyridyl H 1392 6-COCH₃ CF₃ C≡C-4-Pyridyl H 1393 6-COCH₃ CF₃ C≡C-2-furanyl H 1394 6-COCH₃ CF₃ C≡C-3-furanyl H 1395 6-COCH₃ CF₃ C≡C-2-thienyl H 1396 6-COCH₃ CF₃ C≡C-3-thienyl H 1397 6-NH₂ CF₃ C≡C-cycPr H 1398 6-NH₂ CF₃ C≡C—Ph H 1399 6-NH₂ CF₃ C≡C-2-Pyridyl H 1400 6-NH₂ CF₃ C≡C-3-Pyridyl H 1401 6-NH₂ CF₃ C≡C-4-Pyridyl H 1402 6-NH₂ CF₃ C≡C-2-furanyl H 1403 6-NH₂ CF₃ C≡C-3-furanyl H 1404 6-NH₂ CF₃ C≡C-2-thienyl H 1405 6-NH₂ CF₃ C≡C-3-thienyl H 1406 6-NMe₂ CF₃ C≡C-cycPr H 1407 6-NMe₂ CF₃ C≡C—Ph H 1408 6-NMe₂ CF₃ C≡C-2-Pyridyl H 1409 6-NMe₂ CF₃ C≡C-3-Pyridyl H 1410 6-NMe₂ CF₃ C≡C-4-Pyridyl H 1411 6-NMe₂ CF₃ C≡C-2-furanyl H 1412 6-NMe₂ CF₃ C≡C-3-furanyl H 1413 6-NMe₂ CF₃ C≡C-2-thienyl H 1414 6-NMe₂ CF₃ C≡C-3-thienyl H 1415 7-Cl CF₃ C≡C-cycPr H 1416 7-Cl CF₃ C≡C—Ph H 1417 7-Cl CF₃ C≡C-2-Pyridyl H 1418 7-Cl CF₃ C≡C-3-Pyridyl H 1419 7-Cl CF₃ C≡C-4-Pyridyl H 1420 7-Cl CF₃ C≡C-2-furanyl H 1421 7-Cl CF₃ C≡C-3-furanyl H 1422 7-Cl CF₃ C≡C-2-thienyl H 1423 7-Cl CF₃ C≡C-3-thienyl H 1424 5,6-OCH₂O— CF₃ C≡C-cycPr H 1425 5,6-OCH₂O— CF₃ C≡CCH₂CH₂OH H 1426 5,6-OCH₂O— CF₃ C≡C—CH(OH)Me H 1427 5,6-OCH₂O— CF₃ C≡C—Ph H 1428 5,6-OCH₂O— CF₃ C≡C-(2-Cl)Ph H 1429 5,6-OCH₂O— CF₃ C≡C-(3-Cl)Ph H 1430 5,6-OCH₂O— CF₃ C≡C-(4-Cl)Ph H 1431 5,6-OCH₂O— CF₃ C≡C-(2-F)Ph H 1432 5,6-OCH₂O— CF₃ C≡C-(3-F)Ph H 1433 5,6-OCH₂O— CF₃ C≡C-(4-F)Ph H 1434 5,6-OCH₂O— CF₃ C≡C-(2-OH)Ph H 1435 5,6-OCH₂O— CF₃ C≡C-(3-OH)Ph H 1436 5,6-OCH₂O— CF₃ C≡C-(4-OH)Ph H 1437 5,6-OCH₂O— CF₃ C≡C-(2-OMe)Ph H 1438 5,6-OCH₂O— CF₃ C≡C-(3-OMe)Ph H 1439 5,6-OCH₂O— CF₃ C≡C-(4-OMe)Ph H 1440 5,6-OCH₂O— CF₃ C≡C-(2-CN)Ph H 1441 5,6-OCH₂O— CF₃ C≡C-(3-CN)Ph H 1442 5,6-OCH₂O— CF₃ C≡C-(4-CN)Ph H 1443 5,6-OCH₂O— CF₃ C≡C-(2-NO₂)Ph H 1444 5,6-OCH₂O— CF₃ C≡C-(3-NO₂)Ph H 1445 5,6-OCH₂O— CF₃ C≡C-(4-NO₂)Ph H 1446 5,6-OCH₂O— CF₃ C≡C-(2-NH₂)Ph H 1447 5,6-OCH₂O— CF₃ C≡C-(3-NH₂)Ph H 1448 5,6-OCH₂O— CF₃ C≡C-(4-NH₂)Ph H 1449 5,6-OCH₂O— CF₃ C≡C-(2-NMe₂)Ph H 1450 5,6-OCH₂O— CF₃ C≡C-(3-NMe₂)Ph H 1451 5,6-OCH₂O— CF₃ C≡C-(4-NMe₂)Ph H 1452 5,6-OCH₂O— CF₃ C≡C-2-Pyridyl H 1453 5,6-OCH₂O— CF₃ C≡C-2-Pyridyl H 1454 5,6-OCH₂O— CF₃ C≡C-3-Pyridyl H 1455 5,6-OCH₂O— CF₃ C≡C-4-Pyridyl H 1456 5,6-OCH₂O— CF₃ C≡C-2-furanyl H 1457 5,6-OCH₂O— CF₃ C≡C-3-furanyl H 1458 5,6-OCH₂O— CF₃ C≡C-2-thienyl H 1459 5,6-OCH₂O— CF₃ C≡C-3-thienyl H 1460 5,6-OCH₂O— CF₃ C≡C-2-oxazolyl H 1461 5,6-OCH₂O— CF₃ C≡C-2-thiazolyl H 1462 5,6-OCH₂O— CF₃ C≡C-4-isoxazolyl H 1463 5,6-OCH₂O— CF₃ C≡C-2-imidazolyl H 1464 6-COCH₃ CF₃ C═C-cycPr H 1465 6-COCH₃ CF₃ C═C—Ph H 1466 6-COCH₃ CF₃ C═C-2-Pyridyl H 1467 6-COCH₃ CF₃ C═C-3-Pyridyl H 1468 6-COCH₃ CF₃ C═C-4-Pyridyl H 1469 6-COCH₃ CF₃ C═C-2-furanyl H 1470 6-COCH₃ CF₃ C═C-3-furanyl H 1471 6-COCH₃ CF₃ C═C-2-thienyl H 1472 6-COCH₃ CF₃ C═C-3-thienyl H 1473 6-NH₂ CF₃ C═C-cycPr H 1474 6-NH₂ CF₃ C═C—Ph H 1475 6-NH₂ CF₃ C═C-2-Pyridyl H 1476 6-NH₂ CF₃ C═C-3-Pyridyl H 1477 6-NH₂ CF₃ C═C-4-Pyridyl H 1478 6-NH₂ CF₃ C═C-2-furanyl H 1479 6-NH₂ CF₃ C═C-3-furanyl H 1480 6-NH₂ CF₃ C═C-2-thienyl H 1481 6-NH₂ CF₃ C═C-3-thienyl H 1482 6-NMe₂ CF₃ C═C-cycPr H 1483 6-NMe₂ CF₃ C═C—Ph H 1484 6-NMe₂ CF₃ C═C-2-Pyridyl H 1485 6-NMe₂ CF₃ C═C-3-Pyridyl H 1486 6-NMe₂ CF₃ C═C-4-Pyridyl H 1487 6-NMe₂ CF₃ C═C-2-furanyl H 1488 6-NMe₂ CF₃ C═C-3-furanyl H 1489 6-NMe₂ CF₃ C═C-2-thienyl H 1490 6-NMe₂ CF₃ C═C-3-thienyl H 1491 7-Cl CF₃ C═C-cycPr H 1492 7-Cl CF₃ C═C—Ph H 1493 7-Cl CF₃ C═C-2-Pyridyl H 1494 7-Cl CF₃ C═C-3-Pyridyl H 1495 7-Cl CF₃ C═C-4-Pyridyl H 1496 7-Cl CF₃ C═C-2-furanyl H 1497 7-Cl CF₃ C═C-3-furanyl H 1498 7-Cl CF₃ C═C-2-thienyl H 1499 7-Cl CF₃ C═C-3-thienyl H 1500 5,6-OCH₂O— CF₃ C═C-cycPr H 1501 5,6-OCH₂O— CF₃ C═CCH₂CH₂OH H 1502 5,6-OCH₂O— CF₃ C═C—CH(OH)Me H 1503 5,6-OCH₂O— CF₃ C═C—Ph H 1504 5,6-OCH₂O— CF₃ C═C-(2-Cl)Ph H 1505 5,6-OCH₂O— CF₃ C═C-(3-Cl)Ph H 1506 5,6-OCH₂O— CF₃ C═C-(4-Cl)Ph H 1507 5,6-OCH₂O— CF₃ C═C-(2-F)Ph H 1508 5,6-OCH₂O— CF₃ C═C-(3-F)Ph H 1509 5,6-OCH₂O— CF₃ C═C-(4-F)Ph H 1510 5,6-OCH₂O— CF₃ C═C-(2-OH)Ph H 1511 5,6-OCH₂O— CF₃ C═C-(3-OH)Ph H 1512 5,6-OCH₂O— CF₃ C═C-(4-OH)Ph H 1513 5,6-OCH₂O— CF₃ C═C-(2-OMe)Ph H 1514 5,6-OCH₂O— CF₃ C═C-(3-OMe)Ph H 1515 5,6-OCH₂O— CF₃ C═C-(4-OMe)Ph H 1516 5,6-OCH₂O— CF₃ C═C-(2-CN)Ph H 1517 5,6-OCH₂O— CF₃ C═C-(3-CN)Ph H 1518 5,6-OCH₂O— CF₃ C═C-(4-CN)Ph H 1519 5,6-OCH₂O— CF₃ C═C-(2-NO₂)Ph H 1520 5,6-OCH₂O— CF₃ C═C-(3-NO₂)Ph H 1521 5,6-OCH₂O— CF₃ C═C-(4-NO₂)Ph H 1522 5,6-OCH₂O— CF₃ C═C-(2-NH₂)Ph H 1523 5,6-OCH₂O— CF₃ C═C-(3-NH₂)Ph H 1524 5,6-OCH₂O— CF₃ C═C-(4-NH₂)Ph H 1525 5,6-OCH₂O— CF₃ C═C-(2-NMe₂)Ph H 1526 5,6-OCH₂O— CF₃ C═C-(3-NMe₂)Ph H 1527 5,6-OCH₂O— CF₃ C═C-(4-NMe₂)Ph H 1528 5,6-OCH₂O— CF₃ C═C-2-Pyridyl H 1529 5,6-OCH₂O— CF₃ C═C-2-Pyridyl H 1530 5,6-OCH₂O— CF₃ C═C-3-Pyridyl H 1531 5,6-OCH₂O— CF₃ C═C-4-Pyridyl H 1532 5,6-OCH₂O— CF₃ C═C-2-furanyl H 1533 5,6-OCH₂O— CF₃ C═C-3-furanyl H 1534 5,6-OCH₂O— CF₃ C═C-2-thienyl H 1535 5,6-OCH₂O— CF₃ C═C-3-thienyl H 1536 5,6-OCH₂O— CF₃ C═C-2-oxazolyl H 1537 5,6-OCH₂O— CF₃ C═C-2-thiazolyl H 1538 5,6-OCH₂O— CF₃ C═C-4-isoxazolyl H 1539 5,6-OCH₂O— CF₃ C═C-2-imidazolyl H 1540 5,6-OCH₂O— CF₃ CH₂CH₂-cycPr H 1541 5,6-OCH₂O— CF₃ CH₂CH₂CH₂CH₂OH H 1542 5,6-OCH₂O— CF₃ CH₂CH₂—CH(OH)Me H 1543 5,6-OCH₂O— CF₃ CH₂CH₂Ph H 1544 5,6-OCH₂O— CF₃ CH₂CH₂-(2-Cl)Ph H 1545 5,6-OCH₂O— CF₃ CH₂CH₂-(3-Cl)Ph H 1546 5,6-OCH₂O— CF₃ CH₂CH₂-(4-Cl)Ph H 1547 5,6-OCH₂O— CF₃ CH₂CH₂-(2-F)Ph H 1548 5,6-OCH₂O— CF₃ CH₂CH₂-(3-F)Ph H 1549 5,6-OCH₂O— CF₃ CH₂CH₂-(4-F)Ph H 1550 5,6-OCH₂O— CF₃ CH₂CH₂-(2-OH)Ph H 1551 5,6-OCH₂O— CF₃ CH₂CH₂-(3-OH)Ph H 1552 5,6-OCH₂O— CF₃ CH₂CH₂-(4-OH)Ph H 1553 5,6-OCH₂O— CF₃ CH₂CH₂-(2-OMe)Ph H 1554 5,6-OCH₂O— CF₃ CH₂CH₂-(3-OMe)Ph H 1555 5,6-OCH₂O— CF₃ CH₂CH₂-(4-OMe)Ph H 1556 5,6-OCH₂O— CF₃ CH₂CH₂-(2-CN)Ph H 1557 5,6-OCH₂O— CF₃ CH₂CH₂-(3-CN)Ph H 1558 5,6-OCH₂O— CF₃ CH₂CH₂-(4-CN)Ph H 1559 5,6-CCH₂O— CF₃ CH₂CH₂-(2-NO₂)Ph H 1560 5,6-OCH₂O— CF₃ CH₂CH₂-(3-NO₂)Ph H 1561 5,6-OCH₂O— CF₃ CH₂CH₂-(4-NO₂)Ph H 1562 5,6-OCH₂O— CF₃ CH₂CH₂-(2-NH₂)Ph H 1563 5,6-OCH₂O— CF₃ CH₂CH₂-(3-NH₂)Ph H 1564 5,6-OCH₂O— CF₃ CH₂CH₂-(4-NH₂)Ph H 1565 5,6-OCH₂O— CF₃ CH₂CH₂-(2-NMe₂)Ph H 1566 5,6-OCH₂O— CF₃ CH₂CH₂-(3-NMe₂)Ph H 1567 5,6-OCH₂O— CF₃ CH₂CH₂-(4-NMe₂)Ph H 1568 5,6-OCH₂O— CF₃ CH₂CH₂-2-Pyridyl H 1569 5,6-OCH₂O— CF₃ CH₂CH₂-3-Pyridyl H 1570 5,6-OCH₂O— CF₃ CH₂CH₂-4-Pyridyl H 1571 5,6-OCH₂O— CF₃ CH₂CH₂-2-furanyl H 1572 5,6-OCH₂O— CF₃ CH₂CH₂-3-furanyl H 1573 5,6-OCH₂O— CF₃ CH₂CH₂-2-thienyl H 1574 5,6-OCH₂O— CF₃ CH₂CH₂-3-thienyl H 1575 5,6-OCH₂O— CF₃ CH₂CH₂-2-oxazolyl H 1576 5,6-OCH₂O— CF₃ CH₂CH₂-2-thiazolyl H 1577 5,6-OCH₂O— CF₃ CH₂CH₂-4-isoxazolyl H 1578 5,6-OCH₂O— CF₃ CH₂CH₂-2-imidazolyl H 1579 5,6-OCH₂O— CF₃ C≡C-cycPr CH₃ 1580 5,6-OCH₂O— CF₃ C≡C—Ph CH₃ 1581 5,6-OCH₂O— CF₃ C≡C-2-Pyridyl CH₃ 1582 5,6-OCH₂O— CF₃ C≡C-3-Pyridyl CH₃ 1583 5,6-OCH₂O— CF₃ C≡C-4-Pyridyl CH₃ 1584 5,6-OCH₂O— CF₃ C≡C-2-furanyl CH₃ 1585 5,6-OCH₂O— CF₃ C≡C-3-furanyl CH₃ 1586 5,6-OCH₂O— CF₃ C≡C-2-thienyl CH₃ 1587 5,6-OCH₂O— CF₃ C≡C-3-thienyl CH₃ 1588 5,6-OCH₂O— CF₃ C═C-cycPr CH₃ 1589 5,6-OCH₂O— CF₃ C═C—Ph CH₃ 1590 5,6-OCH₂O— CF₃ C═C-2-Pyridyl CH₃ 1591 5,6-OCH₂O— CF₃ C═C-3-Pyridyl CH₃ 1592 5,6-OCH₂O— CF₃ C═C-4-Pyridyl CH₃ 1593 5,6-OCH₂O— CF₃ C═C-2-furanyl CH₃ 1594 5,6-OCH₂O— CF₃ C═C-3-furanyl CH₃ 1595 5,6-OCH₂O— CF₃ C═C-2-thienyl CH₃ 1596 5,6-OCH₂O— CF₃ C═C-3-thienyl CH₃ 1597 5,6-OCH₂O— CF₃ CH₂CH₂-cycPr CH₃ 1598 5,6-OCH₂O— CF₃ CH₂CH₂—Ph CH₃ 1599 5,6-OCH₂O— CF₃ CH₂CH₂-2-Pyridyl CH₃ 1600 5,6-OCH₂O— CF₃ CH₂CH₂-3-Pyridyl CH₃ 1601 5,6-OCH₂O— CF₃ CH₂CH₂-4-Pyridyl CH₃ 1602 5,6-OCH₂O— CF₃ CH₂CH₂-2-furanyl CH₃ 1603 5,6-OCH₂O— CF₃ CH₂CH₂-3-furanyl CH₃ 1604 5,6-OCH₂O— CF₃ CH₂CH₂-2-thienyl CH₃ 1605 5,6-OCH₂O— CF₃ CH₂CH₂-3-thienyl CH₃ 1606 5,6-OCH₂O— CF₃ C≡C-cycPr CH₂CH₃ 1607 5,6-OCH₂O— CF₃ C≡C—Ph CH₂CH₃ 1608 5,6-OCH₂O— CF₃ C≡C-2-Pyridyl CH₂CH₃ 1609 5,6-OCH₂O— CF₃ C≡C-3-Pyridyl CH₂CH₃ 1610 5,6-OCH₂O— CF₃ C≡C-4-Pyridyl CH₂CH₃ 1611 5,6-OCH₂O— CF₃ C≡C-2-furanyl CH₂CH₃ 1612 5,6-OCH₂O— CF₃ C≡C-3-furanyl CH₂CH₃ 1613 5,6-OCH₂O— CF₃ C≡C-2-thienyl CH₂CH₃ 1614 5,6-OCH₂O— CF₃ C≡C-3-thienyl CH₂CH₃ 1615 5,6-OCH₂O— CF₃ C═C-cycPr CH₂CH₃ 1616 5,6-OCH₂O— CF₃ C═C—Ph CH₂CH₃ 1617 5,6-OCH₂O— CF₃ C═C-2-Pyridyl CH₂CH₃ 1618 5,6-OCH₂O— CF₃ C═C-3-Pyridyl CH₂CH₃ 1619 5,6-OCH₂O— CF₃ C═C-4-Pyridyl CH₂CH₃ 1620 5,6-OCH₂O— CF₃ C═C-2-furanyl CH₂CH₃ 1621 5,6-OCH₂O— CF₃ C═C-3-furanyl CH₂CH₃ 1622 5,6-OCH₂O— CF₃ C═C-2-thienyl CH₂CH₃ 1623 5,6-OCH₂O— CF₃ C═C-3-thienyl CH₂CH₃ 1624 5,6-OCH₂O— CF₃ CH₂CH₂-cycPr CH₂CH₃ 1625 5,6-OCH₂O— CF₃ CH₂CH₂—Ph CH₂CH₃ 1626 5,6-OCH₂O— CF₃ CH₂CH₂-2-Pyridyl CH₂CH₃ 1627 5,6-OCH₂O— CF₃ CH₂CH₂-3-Pyridyl CH₂CH₃ 1628 5,6-OCH₂O— CF₃ CH₂CH₂-4-Pyridyl CH₂CH₃ 1629 5,6-OCH₂O— CF₃ CH₂CH₂-2-furanyl CH₂CH₃ 1630 5,6-OCH₂O— CF₃ CH₂CH₂-3-furanyl CH₂CH₃ 1631 5,6-OCH₂O— CF₃ CH₂CH₂-2-thienyl CH₂CH₃ 1632 5,6-OCH₂O— CF₃ CH₂CH₂-3-thienyl CH₂CH₃ *Unless otherwise indicated, stereochemisty is (+/−).

TABLE 3*

Ex. # R³ R¹ R² R⁸ 1 6-Cl CF₃ C≡C—Pr H 2 6-Cl CF₃ C≡C—Bu H 3 6-Cl CF₃ C≡C-iBu H 4 6-Cl CF₃ C≡C-tBu H 5 6-Cl CF₃ C≡C—Me H 6 6-Cl CF₃ CH₂CH₂CH₂CH₂CH₃ H 7 6-Cl CF₃ CH₂CH₂CH(CH₃)₂ H 8 6-Cl CF₃ CH₂CH₂CH₂CH₃ H 9 6-Cl CF₃ CH₂CH₂CH₃ H 10 6-Cl CF₃ CH₂CH₂-tBu H 11 6-Cl CF₃ CH₂C≡C—CH₃ H 12 6-Cl CF₃ CH₂C≡C—CH₂CH₃ H 13 6-Cl CF₃ C≡C-iPr CH₃ 14 6-Cl CF₃ C≡C—Pr CH₃ 15 6-Cl CF₃ C≡C—Bu CH₃ 16 6-Cl CF₃ C≡C-iBu CH₃ 17 6-Cl CF₃ C≡C-tBu CH₃ 18 6-Cl CF₃ C≡C—Et CH₃ 19 6-Cl CF₃ C≡C—Me CH₃ 20 6-Cl CF₃ CH₂C≡C—CH₃ CH₃ 21 6-Cl CF₃ CH₂C≡C—CH₂CH₃ CH₃ 22 6-Cl CF₃ CH₂CH₂CH(CH₃)₂ CH₃ 23 6-Cl CF₃ CH₂CH₂CH₂CH₃ CH₃ 24 6-Cl CF₃ CH₂CH₂CH₃ CH₃ 25 6-Cl CF₃ CH₂CH₂-tBu CH₃ 26 6-Cl CF₃ C≡C-iPr CH₂CH₃ 27 6-Cl CF₃ C≡C—Pr CH₂CH₃ 28 6-Cl CF₃ C≡C—Bu CH₂CH₃ 29 6-Cl CF₃ C≡C-iBu CH₂CH₃ 30 6-Cl CF₃ C≡C-tBu CH₂CH₃ 31 6-Cl CF₃ C≡C—Et CH₂CH₃ 32 6-Cl CF₃ C≡C—Me CH₂CH₃ 33 6-Cl CF₃ CH₂C≡C—CH₃ CH₂CH₃ 34 6-Cl CF₃ CH₂C≡C—CH₂CH₃ CH₂CH₃ 35 6-Cl CF₃ CH₂CH₂CH(CH₃)₂ CH₂CH₃ 36 6-Cl CF₃ CH₂CH₂CH₂CH₃ CH₂CH₃ 37 6-Cl CF₃ CH₂CH₂CH₃ CH₂CH₃ 38 6-Cl CF₃ CH₂CH₂-tBu CH₂CH₃ 39 6-MeO CF₃ C≡C—Pr H 40 6-MeO CF₃ C≡C—Bu H 41 6-MeO CF₃ C≡C-iBu H 42 6-MeO CF₃ C≡C-tBu H 43 6-MeO CF₃ C≡C—Et H 44 6-MeO CF₃ C≡C—Me H 45 6-MeO CF₃ CH₂C≡C—CH₃ H 46 6-MeO CF₃ CH₂C≡C—CH₂CH₃ H 47 6-MeO CF₃ CH₂CH₂CH₂CH₂CH₃ H 48 6-MeO CF₃ CH₂CH₂CH(CH₃)₂ H 49 6-MeO CF₃ CH₂CH₂CH₂CH₃ H 50 6-MeO CF₃ CH₂CH₂CH₃ H 51 6-MeO CF₃ CH₂CH₂-tBu H 52 6-MeO CF₃ CH₂C≡C—CH₃ H 53 6-MeO CF₃ CH₂C≡C—CH₂CH₃ H 54 6-MeO CF₃ C≡C-iPr CH₃ 55 6-MeO CF₃ C≡C—Pr CH₃ 56 6-MeO CF₃ C≡C—Bu CH₃ 57 6-MeO CF₃ C≡C-iBu CH₃ 58 6-MeO CF₃ C≡C-tBu CH₃ 59 6-MeO CF₃ C≡C—Et CH₃ 60 6-MeO CF₃ C≡C—Me CH₃ 61 6-MeO CF₃ CH₂C≡C—CH₃ CH₃ 62 6-MeO CF₃ CH₂C≡C—CH₂CH₃ CH₃ 63 6-MeO CF₃ CH₂CH₂CH(CH₃)₂ CH₃ 64 6-MeO CF₃ CH₂CH₂CH₂CH₃ CH₃ 65 6-MeO CF₃ CH₂CH₂CH₃ CH₃ 66 6-MeO CF₃ CH₂CH₂-tBu CH₃ 67 6-MeO CF₃ C≡C-iPr CH₂CH₃ 68 6-MeO CF₃ C≡C—Pr CH₂CH₃ 69 6-MeO CF₃ C≡C—Bu CH₂CH₃ 70 6-MeO CF₃ C≡C-iBu CH₂CH₃ 71 6-MeO CF₃ C≡C-tBu CH₂CH₃ 72 6-MeO CF₃ C≡C—Et CH₂CH₃ 73 6-MeO CF₃ C≡C—Me CH₂CH₃ 74 6-MeO CF₃ CH₂C≡C—CH₃ CH₂CH₃ 75 6-MeO CF₃ CH₂C≡C—CH₂CH₃ CH₂CH₃ 76 6-MeO CF₃ CH₂CH₂CH(CH₃)₂ CH₂CH₃ 77 6-MeO CF₃ CH₂CH₂CH₂CH₃ CH₂CH₃ 78 6-MeO CF₃ CH₂CH₂CH₃ CH₂CH₃ 79 6-MeO CF₃ CH₂CH₂-tBu CH₂CH₃ 80 5,6-diF CF₃ C≡C—Pr H 81 5,6-diF CF₃ C≡C—Bu H 82 5,6-diF CF₃ C≡C-iBu H 83 5,6-diF CF₃ C≡C-tBu H 84 5,6-diF CF₃ C≡C—Me H 85 5,6-diF CF₃ CH₂C≡C—CH₃ H 86 5,6-diF CF₃ CH₂C≡C—CH₂CH₃ H 87 5,6-diF CF₃ CH₂CH₂CH₂CH₂CH₃ H 88 5,6-diF CF₃ CH₂CH₂CH₃ H 89 5,6-diF CF₃ CH₂CH₂-tBu H 90 5,6-diF CF₃ C≡C-iPr CH₃ 91 5,6-diF CF₃ C≡C—Pr CH₃ 92 5,6-diF CF₃ C≡C—Bu CH₃ 93 5,6-diF CF₃ C≡C-iBu CH₃ 94 5,6-diF CF₃ C≡C-tBu CH₃ 95 5,6-diF CF₃ C≡C—Et CH₃ 96 5,6-diF CF₃ C≡C—Me CH₃ 97 5,6-diF CF₃ C≡C—Ph CH₃ 98 5,6-diF CF₃ CH₂C≡C—CH₃ CH₃ 99 5,6-diF CF₃ CH₂C≡C—CH₂CH₃ CH₃ 100 5,6-diF CF₃ CH₂CH₂CH(CH₃)₂ CH₃ 101 5,6-diF CF₃ CH₂CH₂CH₂CH₃ CH₃ 102 5,6-diF CF₃ CH₂CH₂CH₃ CH₃ 103 5,6-diF CF₃ CH₂CH₂-tBu CH₃ 104 5,6-diF CF₃ C≡C-iPr CH₂CH₃ 105 5,6-diF CF₃ C≡C—Pr CH₂CH₃ 106 5,6-diF CF₃ C≡C—Bu CH₂CH₃ 107 5,6-diF CF₃ C≡C-iBu CH₂CH₃ 108 5,6-diF CF₃ C≡C-tBu CH₂CH₃ 109 5,6-diF CF₃ C≡C—Et CH₂CH₃ 110 5,6-diF CF₃ C≡C—Me CH₂CH₃ 111 5,6-diF CF₃ CH₂C≡C—CH₃ CH₂CH₃ 112 5,6-diF CF₃ CH₂C≡C—CH₂CH₃ CH₂CH₃ 113 5,6-diF CF₃ CH₂CH₂CH(CH₃)₂ CH₂CH₃ 114 5,6-diF CF₃ CH₂CH₂CH₂CH₃ CH₂CH₃ 115 5,6-diF CF₃ CH₂CH₂CH₃ CH₂CH₃ 116 5,6-diF CF₃ CH₂CH₂-tBu CH₂CH₃ 117 6-F CF₃ C≡C—Pr H 118 6-F CF₃ C≡C—Bu H 119 6-F CF₃ C≡C-iBu H 120 6-F CF₃ C≡C-tBu H 121 6-F CF₃ C≡C—Me H 122 6-F CF₃ CH₂C≡C—CH₂CH₃ H 123 6-F CF₃ CH₂CH₂CH₂CH₂CH₃ H 124 6-F CF₃ CH₂CH₂CH₃ H 125 6-F CF₃ CH₂CH₂-tBu H 126 6-F CF₃ C≡C-iPr CH₃ 127 6-F CF₃ C≡C—Pr CH₃ 128 6-F CF₃ C≡C—Bu CH₃ 129 6-F CF₃ C≡C-iBu CH₃ 130 6-F CF₃ C≡C-tBu CH₃ 131 6-F CF₃ C≡C—Et CH₃ 132 6-F CF₃ C≡C—Me CH₃ 133 6-F CF₃ CH₂C≡C—CH₃ CH₃ 134 6-F CF₃ CH₂C≡C—CH₂CH₃ CH₃ 135 6-F CF₃ CH₂CH₂CH(CH₃)₂ CH₃ 136 6-F CF₃ CH₂CH₂CH₂CH₃ CH₃ 137 6-F CF₃ CH₂CH₂CH₃ CH₃ 138 6-F CF₃ CH₂CH₂-tBu CH₃ 139 6-F CF₃ C≡C-iPr CH₂CH₃ 140 6-F CF₃ C≡C—Pr CH₂CH₃ 141 6-F CF₃ C≡C—Bu CH₂CH₃ 142 6-F CF₃ C≡C-iBu CH₂CH₃ 143 6-F CF₃ C≡C-tBu CH₂CH₃ 144 6-F CF₃ C≡C—Et CH₂CH₃ 145 6-F CF₃ C≡C—Me CH₂CH₃ 146 6-F CF₃ CH₂C≡C—CH₃ CH₂CH₃ 147 6-F CF₃ CH₂C≡C—CH₂CH₃ CH₂CH₃ 148 6-F CF₃ CH₂CH₂CH(CH₃)₂ CH₂CH₃ 149 6-F CF₃ CH₂CH₂CH₂CH₃ CH₂CH₃ 150 6-F CF₃ CH₂CH₂CH₃ CH₂CH₃ 151 6-F CF₃ CH₂CH₂-tBu CH₂CH₃ 152 5-Cl CF₃ C≡C-iPr H 153 5-Cl CF₃ C≡C—Pr H 154 5-Cl CF₃ C≡C—Bu H 155 5-Cl CF₃ C≡C-iBu H 156 5-Cl CF₃ C≡C-tBu H 157 5-Cl CF₃ C≡C—Et H 158 5-Cl CF₃ C≡C—Me H 159 5-Cl CF₃ CH₂C≡C—CH₃ H 160 5-Cl CF₃ CH₂C≡C—CH₂CH₃ H 161 5-Cl CF₃ CH₂CH₂CH₂CH₂CH₃ H 162 5-Cl CF₃ CH₂CH₂CH(CH₃)₂ H 163 5-Cl CF₃ CH₂CH₂CH₂CH₃ H 164 5-Cl CF₃ CH₂CH₂CH₃ H 165 5-Cl CF₃ CH₂CH₂-tBu H 166 5-Cl CF₃ C≡C-iPr CH₃ 167 5-Cl CF₃ C≡C—Pr CH₃ 168 5-Cl CF₃ C≡C—Bu CH₃ 169 5-Cl CF₃ C≡C-iBu CH₃ 170 5-Cl CF₃ C≡C-tBu CH₃ 171 5-Cl CF₃ C≡C—Et CH₃ 172 5-Cl CF₃ C≡C—Me CH₃ 173 5-Cl CF₃ CH₂C≡C—CH₃ CH₃ 174 5-Cl CF₃ CH₂C≡C—CH₂CH₃ CH₃ 175 5-Cl CF₃ CH₂CH₂CH(CH₃)₂ CH₃ 176 5-Cl CF₃ CH₂CH₂CH₂CH₃ CH₃ 177 5-Cl CF₃ CH₂CH₂CH₃ CH₃ 178 5-Cl CF₃ CH₂CH₂-tBu CH₃ 179 5-Cl CF₃ C≡C-iPr CH₂CH₃ 180 5-Cl CF₃ C≡C—Pr CH₂CH₃ 181 5-Cl CF₃ C≡C—Bu CH₂CH₃ 182 5-Cl CF₃ C≡C-iBu CH₂CH₃ 183 5-Cl CF₃ C≡C-tBu CH₂CH₃ 184 5-Cl CF₃ C≡C—Et CH₂CH₃ 185 5-Cl CF₃ C≡C—Me CH₂CH₃ 186 5-Cl CF₃ CH₂C≡C—CH₃ CH₂CH₃ 187 5-Cl CF₃ CH₂C≡C—CH₂CH₃ CH₂CH₃ 188 5-Cl CF₃ CH₂CH₂CH(CH₃)₂ CH₂CH₃ 189 5-Cl CF₃ CH₂CH₂CH₂CH₃ CH₂CH₃ 190 5-Cl CF₃ CH₂CH₂CH₃ CH₂CH₃ 191 5-Cl CF₃ CH₂CH₂-tBu CH₂CH₃ 192 5-F CF₃ C≡C-iPr H 193 5-F CF₃ C≡C—Pr H 194 5-F CF₃ C≡C—Bu H 195 5-F CF₃ C≡C-iBu H 196 5-F CF₃ C≡C-tBu H 197 5-F CF₃ C≡C—Et H 198 5-F CF₃ C≡C—Me H 199 5-F CF₃ CH₂C≡C—CH₃ H 200 5-F CF₃ CH₂C≡C—CH₂CH₃ H 201 5-F CF₃ CH₂CH₂CH₂CH₂CH₃ H 202 5-F CF₃ CH₂CH₂CH(CH₃)₂ H 203 5-F CF₃ CH₂CH₂CH₂CH₃ H 204 5-F CF₃ CH₂CH₂CH₃ H 205 5-F CF₃ CH₂CH₂-tBu H 206 5-F CF₃ C≡C-iPr CH₃ 207 5-F CF₃ C≡C—Pr CH₃ 208 5-F CF₃ C≡C—Bu CH₃ 209 5-F CF₃ C≡C-iBu CH₃ 210 5-F CF₃ C≡C-tBu CH₃ 211 5-F CF₃ C≡C—Et CH₃ 212 5-F CF₃ C≡C—Me CH₃ 213 5-F CF₃ CH₂C≡C—CH₃ CH₃ 214 5-F CF₃ CH₂C≡C—CH₂CH₃ CH₃ 215 5-F CF₃ CH₂CH₂CH(CH₃)₂ CH₃ 216 5-F CF₃ CH₂CH₂CH₂CH₃ CH₃ 217 5-F CF₃ CH₂CH₂CH₃ CH₃ 218 5-F CF₃ CH₂CH₂-tBu CH₃ 219 5-F CF₃ C≡C-iPr CH₂CH₃ 220 5-F CF₃ C≡C—Pr CH₂CH₃ 221 5-F CF₃ C≡C—Bu CH₂CH₃ 222 5-F CF₃ C≡C-iBu CH₂CH₃ 223 5-F CF₃ C≡C-tBu CH₂CH₃ 224 5-F CF₃ C≡C—Et CH₂CH₃ 225 5-F CF₃ C≡C—Me CH₂CH₃ 226 5-F CF₃ CH₂C≡C—CH₃ CH₂CH₃ 227 5-F CF₃ CH₂C≡C—CH₂CH₃ CH₂CH₃ 228 5-F CF₃ CH₂CH₂CH(CH₃)₂ CH₂CH₃ 229 5-F CF₃ CH₂CH₂CH₂CH₃ CH₂CH₃ 230 5-F CF₃ CH₂CH₂CH₃ CH₂CH₃ 231 5-F CF₃ CH₂CH₂-tBu CH₂CH₃ 232 5-Cl, 6-F CF₃ C≡C-iPr H 233 5-Cl, 6-F CF₃ C≡C—Pr H 234 5-Cl, 6-F CF₃ C≡C—Bu H 235 5-Cl, 6-F CF₃ C≡C-iBu H 236 5-Cl, 6-F CF₃ C≡C-tBu H 237 5-Cl, 6-F CF₃ C≡C—Et H 238 5-Cl, 6-F CF₃ C≡C—Me H 239 5-Cl, 6-F CF₃ CH₂C≡C—CH₃ H 240 5-Cl, 6-F CF₃ CH₂C≡CH₂CH₃ H 241 5-Cl, 6-F CF₃ CH₂CH₂CH(CH₃)₂ H 242 5-Cl, 6-F CF₃ CH₂CH₂CH₂CH₃ H 243 5-Cl, 6-F CF₃ CH₂CH₂CH₃ H 244 5-Cl, 6-F CF₃ CH₂CH₂-tBu H 245 5-Cl, 6-F CF₃ C≡C-iPr CH₃ 246 5-Cl, 6-F CF₃ C≡C—Pr CH₃ 247 5-Cl, 6-F CF₃ C≡C—Bu CH₃ 248 5-Cl, 6-F CF₃ C≡C-iBu CH₃ 249 5-Cl, 6-F CF₃ C≡C-tBu CH₃ 250 5-Cl, 6-F CF₃ C≡C—Et CH₃ 251 5-Cl, 6-F CF₃ C≡C—Me CH₃ 252 5-Cl, 6-F CF₃ CH₂C≡C—CH₃ CH₃ 253 5-Cl, 6-F CF₃ CH₂C≡C—CH₂CH₃ CH₃ 254 5-Cl, 6-F CF₃ CH₂CH₂CH(CH₃)₂ CH₃ 255 5-Cl, 6-F CF₃ CH₂CH₂CH₂CH₃ CH₃ 256 5-Cl, 6-F CF₃ CH₂CH₂CH₃ CH₃ 257 5-Cl, 6-F CF₃ CH₂CH₂-tBu CH₃ 258 6-Cl, 8-F CF₃ C≡C-iPr H 259 6-Cl, 8-F CF₃ C≡C—Pr H 260 6-Cl, 8-F CF₃ C≡C—Bu H 261 6-Cl, 8-F CF₃ C≡C-iBu H 262 6-Cl, 8-F CF₃ C≡C-tBu H 263 6-Cl, 8-F CF₃ C≡C—Et H 264 6-Cl, 8-F CF₃ C≡C—Me H 265 6-Cl, 8-F CF₃ CH₂C≡C—CH₃ H 266 6-Cl, 8-F CF₃ CH₂C≡C—CH₂CH₃ H 267 6-Cl, 8-F CF₃ CH₂CH₂CH(CH₃)₂ H 268 6-Cl, 8-F CF₃ CH₂CH₂CH₂CH₃ H 269 6-Cl, 8-F CF₃ CH₂CH₂CH₃ H 270 6-Cl, 8-F CF₃ CH₂CH₂-tBu H 271 6-Cl, 8-F CF₃ C≡C-iPr CH₃ 272 6-Cl, 8-F CF₃ C≡C—Pr CH₃ 273 6-Cl, 8-F CF₃ C≡C—Bu CH₃ 274 6-Cl, 8-F CF₃ C≡C-iBu CH₃ 275 6-Cl, 8-F CF₃ C≡C-tBu CH₃ 276 6-Cl, 8-F CF₃ C≡C—Et CH₃ 277 6-Cl, 8-F CF₃ C≡C—Me CH₃ 278 6-Cl, 8-F CF₃ CH₂C≡C—CH₃ CH₃ 279 6-Cl, 8-F CF₃ CH₂C≡C—CH₂CH₃ CH₃ 280 6-Cl, 8-F CF₃ CH₂CH₂CH(CH₃)₂ CH₃ 281 6-Cl, 8-F CF₃ CH₂CH₂CH₂CH₃ CH₃ 282 6-Cl, 8-F CF₃ CH₂CH₂CH₃ CH₃ 283 6-Cl, 8-F CF₃ CH₂CH₂-tBu CH₃ 284 6-CH₃ CF₃ C≡C-iPr H 285 6-CH₃ CF₃ C≡C—Pr H 286 6-CH₃ CF₃ C≡C—Bu H 287 6-CH₃ CF₃ C≡C-iBu H 288 6-CH₃ CF₃ C≡C-tBu H 289 6-CH₃ CF₃ C≡C—Et H 290 6-CH₃ CF₃ C≡C—Me H 291 6-CH₃ CF₃ CH₂C≡C—CH₃ H 292 6-CH₃ CF₃ CH₂C≡C—CH₂CH₃ H 293 6-CH₃ CF₃ CH₂CH₂CH(CH₃)₂ H 294 6-CH₃ CF₃ CH₂CH₂CH₂CH₃ H 295 6-CH₃ CF₃ CH₂CH₂CH₃ H 296 6-CH₃ CF₃ CH₂CH₂-tBu H 297 6-CH₃ CF₃ C≡C-iPr CH₃ 298 6-CH₃ CF₃ C≡C—Pr CH₃ 299 6-CH₃ CF₃ C≡C—Bu CH₃ 300 6-CH₃ CF₃ C≡C-iBu CH₃ 301 6-CH₃ CF₃ C≡C-tBu CH₃ 302 6-CH₃ CF₃ C≡C—Et CH₃ 303 6-CH₃ CF₃ C≡C—Me CH₃ 304 6-CH₃ CF₃ CH₂C≡C—CH₃ CH₃ 305 6-CH₃ CF₃ CH₂C≡C—CH₂CH₃ CH₃ 306 6-CH₃ CF₃ CH₂CH₂CH(CH₃)₂ CH₃ 307 6-CH₃ CF₃ CH₂CH₂CH₂CH₃ CH₃ 308 6-CH₃ CF₃ CH₂CH₂CH₃ CH₃ 309 6-CH₃ CF₃ CH₂CH₂-tBu CH₃ 310 6-COCH₃ CF₃ C≡C-iPr H 311 6-COCH₃ CF₃ C≡C—Pr H 312 6-COCH₃ CF₃ C≡C—Bu H 313 6-COCH₃ CF₃ C≡C-iBu H 314 6-COCH₃ CF₃ C≡C-tBu H 315 6-COCH₃ CF₃ C≡C—Et H 316 6-COCH₃ CF₃ C≡C—Me H 317 6-NH₂ CF₃ C≡C-iPr H 318 6-NH₂ CF₃ C≡C—Pr H 319 6-NH₂ CF₃ C≡C—Bu H 320 6-NH₂ CF₃ C≡C-iBu H 321 6-NH₂ CF₃ C≡C-tBu H 322 6-NH₂ CF₃ C≡C—Et H 323 6-NH₂ CF₃ C≡C—Me H 324 6-NMe₂ CF₃ C≡C-iPr H 325 6-NMe₂ CF₃ C≡C—Pr H 326 6-NMe₂ CF₃ C≡C—Bu H 327 6-NMe₂ CF₃ C≡C-iBu H 328 6-NMe₂ CF₃ C≡C-tBu H 329 6-NMe₂ CF₃ C≡C—Et H 330 6-NMe₂ CF₃ C≡C—Me H 331 7-Cl CF₃ C≡C-iPr H 332 7-Cl CF₃ C≡C—Pr H 333 7-Cl CF₃ C≡C—Bu H 334 7-Cl CF₃ C≡C-iBu H 335 7-Cl CF₃ C≡C-tBu H 336 7-Cl CF₃ C≡C—Et H 337 7-Cl CF₃ C≡C—Me H *Unless otherwise indicated, stereochemistry is (+/−).

Utility

The compounds of this invention possess reverse transcriptase inhibitory activity, in particular, HIV inhibitory efficacy. The compounds of formula (I) possess HIV reverse transcriptase inhibitory activity and are therefore useful as antiviral agents for the treatment of HIV infection and associated diseases. The compounds of formula (I) possess HIV reverse transcriptase inhibitory activity and are effective as inhibitors of HIV growth. The ability of the compounds of the present invention to inhibit viral growth or infectivity is demonstrated in standard assay of viral growth or infectivity, for example, using the assay described below.

The compounds of formula (I) of the present invention are also useful for the inhibition of HIV in an ex vivo sample containing HIV or expected to be exposed to HIV. Thus, the compounds of the present invention may be used to inhibit HIV present in a body fluid sample (for example, a serum or semen sample) which contains or is suspected to contain or be exposed to HIV.

The compounds provided by this invention are also useful as standard or reference compounds for use in tests or assays for determining the ability of an agent to inhibit viral clone replication and/or HIV reverse transcriptase, for example in a pharmaceutical research program. Thus, the compounds of the present invention may be used as a control or reference compound in such assays and as a quality control standard. The compounds of the present invention may be provided in a commercial kit or container for use as such standard or reference compound.

Since the compounds of the present invention exhibit specificity for HIV reverse transcriptase, the compounds of the present invention may also be useful as diagnostic reagents in diagnostic assays for the detection of HIV reverse transcriptase. Thus, inhibition of the reverse transcriptase activity in an assay (such as the assays described herein) by a compound of the present invention would be indicative of the presence of HIV reverse transcriptase and HIV virus.

As used herein “μg” denotes microgram, “mg” denotes milligram, “g” denotes gram, “μL” denotes microliter, “mL” denotes milliliter, “L” denotes liter, “nM” denotes nanomolar, “μM” denotes micromolar, “mM” denotes millimolar, “M” denotes molar and “mm” denotes nanometer. “Sigma” stands for the Sigma-Aldrich Corp. of St. Louis, Mo.

HIV RNA Assay

DNA Plasmids and In vitro RNA Transcripts:

Plasmid pDAB 72 containing both gag and pol sequences of BH10 (bp 113-1816) cloned into PTZ 19R was prepared according to Erickson-Viitanen et al. AIDS Research and Human Retroviruses 1989, 5, 577. The plasmid was linearized with Ban HI prior to the generation of in vitro RNA transcripts using the Riboprobe Gemini system II kit (Promega) with T7 RNA polymerase. Synthesized RNA was purified by treatment with RNase free DNAse (Promega), phenol-chloroform extraction, and ethanol precipitation. RNA transcripts were dissolved in water, and stored at −70° C. The concentration of RNA was determined from the A₂₆₀.

Probes:

Biotinylated capture probes were purified by HPLC after synthesis on an Applied Biosystems (Foster City, Calif.) DNA synthesizer by addition of biotin to the 5′ terminal end of the oligonucleotide, using the biotin-phosphoramidite reagent of Cocuzza, Tet. Lett. 1989, 30, 6287. The gag biotinylated capture probe (5-biotin-CTAGCTCCCTGCTTGCCCATACTA 3′) was complementary to nucleotides 889-912 of HXB2 and the pol biotinylated capture probe (5′-biotin -CCCTATCATTTTTGGTTTCCAT 3′) was complementary to nucleotides 2374-2395 of HXB2. Alkaline phosphatase conjugated oligonucleotides used as reporter probes were prepared by Syngene (San Diego, Calif.). The pol reporter probe (5′ C.TGTCTTACTTTGATAAAACCTC 3′) was complementary to nucleotides 2403-2425 of HXB2. The gag reporter probe (5′ C.CCAGTATTTGTCTACAGCCTTCT 3′) was complementary to nucleotides 950-973 of HXB2. All nucleotide positions are those of the GenBank Genetic Sequence Data Bank as accessed through the Genetics Computer Group Sequence Analysis Software Package (Devereau Nucleic Acids Research 1984, 12, 387). The reporter probes were prepared as 0.5 μM stocks in 2×SSC (0.3 M NaCl, 0.03 M sodium citrate), 0.05 M Tris pH 8.8, 1 mg/mL BSA. The biotinylated capture probes were prepared as 100 μM stocks in water.

Strentavidin Coated Plates:

Streptavidin coated plates were obtained from Du Pont Biotechnology Systems (Boston, Mass.).

Cells and Virus Stocks:

MT-2 and MT-4 cells were maintained in RPMI 1640 supplemented with 5% fetal calf serum (FCS) for MT-2 cells or 10% FCS for MT-4 cells, 2 mM L-glutamine and 50 μg/mL gentamycin, all from Gibco. HIV-1 RF was propagated in MT-4 cells in the same medium. Virus stocks were prepared approximately 10 days after acute infection of MT-4 cells and stored as aliquots at −70° C. Infectious titers of HIV-1 (RF) stocks were 1-3×10⁷ PFU (plaque forming units)/mL as measured by plaque assay on MT-2 cells (see below). Each aliquot of virus stock used for infection was thawed only once.

For evaluation of antiviral efficacy, cells to be infected were subcultured one day prior to infection. On the day of infection, cells were resuspended at 5×10⁵ cells/mL in RPMI 1640, 5% FCS for bulk infections or at 2×10⁶/mL in Dulbecco's modified Eagles medium with 5% FCS for infection in microtiter plates. Virus was added and culture continued for 3 days at 37° C.

HIV RNA Assay:

Cell lysates or purified RNA in 3 M or 5 M GED were mixed with 5 M GED and capture probe to a final guanidinium isothiocyanate concentration of 3 M and a final biotin oligonucleotide concentration of 30 nM. Hybridization was carried out in sealed U bottom 96 well tissue culture plates (Nunc or Costar) for 16-20 hours at 37° C. RNA hybridization reactions were diluted three-fold with deionized water to a final guanidinium isothiocyanate concentration of 1 M and aliquots (150 μL) were transferred to streptavidin coated microtiter plates wells. Binding of capture probe and capture probe-RNA hybrid to the immobilized streptavidin was allowed to proceed for 2 hours at room temperature, after which the plates were washed 6 times with DuPont ELISA plate wash buffer (phosphate buffered saline(PBS), 0.05% Tween 20.) A second hybridization of reporter probe to the immobilized complex of capture probe and hybridized target RNA was carried out in the washed streptavidin coated well by addition of 120 μl of a hybridization cocktail containing 4×SSC, 0.66% Triton X 100, 6.66% deionized formamide, 1 mg/mL BSA and 5 nM reporter probe. After hybridization for one hour at 37° C., the plate was again washed 6 times. Immobilized alkaline phosphatase activity was detected by addition of 100 μL of 0.2 mM 4-methylumbelliferyl phosphate (MUBP, JBL Scientific) in buffer δ (2.5 M diethanolamine pH 8.9 (JBL Scientific), 10 mM MgCl₂, 5 mM zinc acetate dihydrate and 5 mM N-hydroxyethyl-ethylene-diamine-triacetic acid). The plates were incubated at 37° C. Fluorescence at 450 nM was measured using a microplate fluorometer (Dynateck) exciting at 365 nM.

Microtlate Based Compound Evaluation in HIV-1 Infected MT-2 Cells:

Compounds to be evaluated were dissolved in DMSO and diluted in culture medium to twice the highest concentration to be tested and a maximum DMSO concentration of 2%. Further three-fold serial dilutions of the compound in culture medium were performed directly in U bottom microtiter plates (Nunc). After compound dilution, MT-2 cells (50 μL) were added to a final concentration of 5×10⁵ per mL (1×10⁵ per well). Cells were incubated with compounds for 30 minutes at 37° C. in a CO₂ incubator. For evaluation of antiviral potency, an appropriate dilution of HIV-1 (RF) virus stock (50 μL) was added to culture wells containing cells and dilutions of the test compounds. The final volume in each well was 200 μL. Eight wells per plate were left uninfected with 50 μL of medium added in place of virus, while eight wells were infected in the absence of any antiviral compound. For evaluation of compound toxicity, parallel plates were cultured without virus infection.

After 3 days of culture at 37° C. in a humidified chamber inside a CO₂ incubator, all but 25 μL of medium/well was removed from the HIV infected plates. Thirty seven μL of 5 M GED containing biotinylated capture probe was added to the settled cells and remaining medium in each well to a final concentration of 3 M GED and 30 nM capture probe. Hybridization of the capture probe to HIV RNA in the cell lysate was carried out in the same microplate well used for virus culture by sealing the plate with a plate sealer (Costar), and incubating for 16-20 hrs in a 37° C. incubator. Distilled water was then added to each well to dilute the hybridization reaction three-fold and 150 μL of this diluted mixture was transferred to a streptavidin coated microtiter plate. HIV RNA was quantitated as described above. A standard curve, prepared by adding known amounts of pDAB 72 in vitro RNA transcript to wells containing lysed uninfected cells, was run on each microtiter plate in order to determine the amount of viral RNA made during the infection.

In order to standardize the virus inoculum used in the evaluation of compounds for antiviral activity, dilutions of virus were selected which resulted in an IC₉₀ value (concentration of compound required to reduce the HIV RNA level by 90%) for dideoxycytidine (ddC) of 0.2 μg/mL. IC₉₀ values of other antiviral compounds, both more and less potent than ddC, were reproducible using several stocks of HIV-1 (RF) when this procedure was followed. This concentration of virus corresponded to ˜3×10⁵ PFU (measured by plaque assay on MT-2 cells) per assay well and typically produced approximately 75% of the maximum viral RNA level achievable at any virus inoculum. For the HIV RNA assay, IC₉₀ values were determined from the percent reduction of net signal (signal from infected cell samples minus signal from uninfected cell samples) in the RNA assay relative to the net signal from infected, untreated cells on the same culture plate (average of eight wells). Valid performance of individual infection and RNA assay tests was judged according to three criteria. It was required that the virus infection should result in an RNA assay signal equal to or greater than the signal generated from 2 ng of pDAB 72 in vitro RNA transcript. The IC₉₀ for ddC, determined in each assay run, should be between 0.1 and 0.3 μg/mL. Finally, the plateau level of viral RNA produced by an effective reverse transcriptase inhibitor should be less than 10% of the level achieved in an uninhibited infection. A compound was considered active if its IC₉₀ was found to be less than 20 μM.

For antiviral potency tests, all manipulations in microtiter plates, following the initial addition of 2× concentrated compound solution to a single row of wells, were performed using a Perkin Elmer/Cetus ProPette.

Protein Binding and Mutant Resistance

In order to characterize NNRTI analogs for their clinical efficacy potential the effect of plasma proteins on antiviral potency and measurements of antiviral potency against wild type and mutant variants of HIV which carry amino acid changes in the known binding site for NNRTIs were examined. The rationale for this testing strategy is two fold:

1. Many drugs are extensively bound to plasma proteins. Although the binding affinity for most drugs for the major components of human plasma, namely, human serum albumin (HSA) or alpha-1-acid glycoprotein (AAG), is low, these major components are present in high concentration in the blood. Only free or unbound drug is available to cross the infected cell membrane for interaction with the target site (i.e., HIV-1 reverse transcriptase, HIV-1 RT). Therefore, the effect of added HSA+AAG on the antiviral potency in tissue culture more closely reflects the potency of a given compound in the clinical setting. The concentration of compound required for 90% inhibition of virus replication as measured in a sensitive viral RNA-based detection method is designated the IC90. The fold increase in apparent IC90 for test compounds in the presence or added levels of HSA and AAG that reflect in vivo concentrations (45 mg/ml HSA, 1 mg/ml AAG) was then calculated. The lower the fold increase, the more compound will be available to interact with the target site.

2. The combination of the high rate of virus replication in the infected individual and the poor fidelity of the viral RT results in the production of a quasi-species or mixtures of HIV species in the infected individual. These species will include a majority wild type species, but also mutant variants of HIV and the proportion of a given mutant will reflect its relative fitness and replication rate. Because mutant variants including mutants with changes in the amino acid sequence of the viral RT likely pre-exist in the infected individual's quasi-speciesi, the overall potency observed in the clinical setting will reflect the ability of a drug to inhibit not only wild type HIV-1, but mutant variants as well. We thus have constructed, in a known genetic background, mutant variants of HIV-1 which carry amino acid substitutions at positions thought to be involved in NNRTI binding, and measured the ability of test compounds to inhibit replication of these mutant viruses. The concentration of compound required for 90% inhibition of virus replication as measured in a sensitive viral RNA-based detection method is designated the IC90. It is desirable to have a compound which has high activity against a variety of mutants.

Dosaae and Formulation

The antiviral compounds of this invention can be administered as treatment for viral infections by any means that produces contact of the active agent with the agent's site of action, i.e., the viral reverse transcriptase, in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but preferably are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired. A daily dosage of active ingredient can be expected to be about 0.001 to about 1000 milligrams per kilogram of body weight, with the preferred dose being about 0.1 to about 30 mg/kg.

Dosage forms of compositions suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts, and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, supra, a standard reference text in this field.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg magnesium stearic.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil can be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules should then be washed and dried.

Tablets

A large number of tablets can be prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Suspension

An aqueous suspension can be prepared for oral administration so that each 5 mL contain 25 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mg of vanillin.

Injectable

A parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is sterilized by commonly used techniques.

Combination of Components (a) and (b)

Each therapeutic agent component of this invention can independently be in any dosage form, such as those described above, and can also be administered in various ways, as described above. In the following description component (b) is to be understood to represent one or more agents as described previously. Thus, if components (a) and (b) are to be treated the same or independently, each agent of component (b) may also be treated the same or independently.

Components (a) and (b) of the present invention may be formulated together, in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.) as a combination product. When component (a) and (b) are not formulated together in a single dosage unit, the component (a) may be administered at the same time as component (b) or in any order; for example component (a) of this invention may be administered first, followed by administration of component (b), or they may be administered in the revserse order. If component (b) contains more that one agent, e.g., one RT inhibitor and one protease inhibitor, these agents may be administered together or in any order. When not administered at the same time, preferably the administration of component (a) and (b) occurs less than about one hour apart. Preferably, the route of administration of component (a) and (b) is oral. The terms oral agent, oral inhibitor, oral compound, or the like, as used herein, denote compounds which may be orally administered. Although it is preferable that component (a) and component (b) both be administered by the same route (that is, for example, both orally) or dosage form, if desired, they may each be administered by different routes (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously) or dosage forms.

As is appreciated by a medical practitioner skilled in the art, the dosage of the combination therapy of the invention may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, and the effect desired, as described above.

The proper dosage of components (a) and (b) of the present invention will be readily ascertainable by a medical practitioner skilled in the art, based upon the present disclosure. By way of general guidance, typically a daily dosage may be about 100 milligrams to about 1.5 grams of each component. If component (b) represents more than one compound, then typically a daily dosage may be about 100 milligrams to about 1.5 grams of each agent of component (b). By way of general guidance, when the compounds of component (a) and component (b) are administered in combination, the dosage amount of each component may be reduced by about 70-80% relative to the usual dosage of the component when it is administered alone as a single agent for the treatment of HIV infection, in view of the synergistic effect of the combination.

The combination products of this invention may be formulated such that, although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized. In order to minimize contact, for example, where the product is orally administered, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. Another embodiment of this invention where oral administration is desired provides for a combination product wherein one of the active ingredients is coated with a sustained-release material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component. In each formulation wherein contact is prevented between components (a) and (b) via a coating or some other material, contact may also be prevented between the individual agents of component (b).

Dosage forms of the combination products of the present invention wherein one active ingredient is enteric coated can be in the form of tablets such that the enteric coated component and the other active ingredient are blended together and then compressed into a tablet or such that the enteric coated component is compressed into one tablet layer and the other active ingredient is compressed into an additional layer. Optionally, in order to further separate the two layers, one or more placebo layers may be present such that the placebo layer is between the layers of active ingredients. In addition, dosage forms of the present invention can be in the form of capsules wherein one active ingredient is compressed into a tablet or in the form of a plurality of microtablets, particles, granules or non-perils, which are then enteric coated. These enteric coated microtablets, particles, granules or non-perils are then placed into a capsule or compressed into a capsule along with a granulation of the other active ingredient.

These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time or concurrently by the same manner, will be readily apparent to those skilled in the art, based on the present disclosure.

Pharmaceutical kits useful for the treatment of HIV infection, which comprise a therapeutically effective amount of a pharmaceutical composition comprising a compound of component (a) and one or more compounds of component (b), in one or more sterile containers, are also within the ambit of the present invention. Sterilization of the container may be carried out using conventional sterilization methodology well known to those skilled in the art. Component (a) and component (b) may be in the same sterile container or in separate sterile containers. The sterile containers of materials may comprise separate containers, or one or more multi-part containers, as desired. Component (a) and component (b), may be separate, or physically combined into a single dosage form or unit as described above. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as for example, one or more pharmaceutically acceptable carriers, additional vials for mixing the components, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit.

Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scopeof the appended claims, the.invention may be practiced otherwise than as specifically described herein. 

What is claimed as new and desired to be secured by Letter Patent of United Stated is:
 1. A method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of: (a) a compound selected from: (−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, (+)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(iH)-quinazolinone, (+)-4-cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, (−)-4-cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, (+)-E-4-cyclopropylethenyl-5,G6-difluoro-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone, and (−)-6-chloro-4-E-cyclopropylethenyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, or stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salts thereof; and, (b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
 2. A method according to claim 1, wherein the reverse transcriptase inhibitor is selected from AZT, 3TC (β-L-3′-thia-2′,3′-dideoxycytidine), ddI, ddC, d4T (2′,3′-didehydro-2′,3′-dideoxythimidine), delavirdine, TIBO (tetrahydroimidazo[4,5,1-jkj] [1,4]benzodiazepin-2(1H)-one and thione) derivatives, nevirapine, L-697,661 (3-[(4,7-Dichlorobenzooxazol-2-ylmethyl)-amino]-5-ethyl-6-methyl-1H-pyridin-2-one), LY 73497 (N-(2-phenylethyl)-N′-(2-thiazolyl)thiourea), loviride, trovirdine, MKC-442 (1-ethoxymethyl-5-isopropyl-6-benzyluracil), and HBY 097 (7-Methoxy-2-methylsulfanylmethyl-3-thioxo-3,4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester), and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478 (amprenavir, 4-amino-N-[2(R)-hydroxy-4-phenyl-3(S)-[tetrahydrofuran-3(S)-yloxycarbonylamino]butyl]-N-isobutylbenzenesulfonamide), nelfinavir, KNI-272 (3-(2-Hydroxy-3-{2-[2-(isoquinolin-5-yloxy)-acetylamino]-3-methylsulfanyl-propionylamino}-4-phenyl-butyryl)-thiazolidine-4-carboxylic acid tert-butylamide), CGP-61755 (lasinavir), U-140690 (5-trifluoromethylpyridine-2-sulfonic acid {3-[1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl]-phenyl}-amide), and ABT-378 (N-(4(S)-(2-(2,6-dimethylphenoxy)-acetylamino)-3(S)-hydroxy-5-phenyl-1(S)-benzylpentyl)-3-methyl-2-(S)-(2-oxo(1,3-diazaperhydroxinyl)butanamine)).
 3. A method according to claim 2, wherein the reverse transcriptase inhibitor is selected from AZT and 3TC and the protease inhibitor is selected from saquinavir, nelfinavir, ritonavir, and indinavir.
 4. The method of claim 1, wherein the compound is (−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
 5. The method of claim 1, wherein the compound is (+)-6-chloro-4- cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
 6. The method of claim 1, wherein the compound is (+)-4-cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
 7. The method of claim 1, wherein the compound is (−)-4-cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
 8. The method of claim 1, wherein the compound is (+)-E-4-cyclopropylethenyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
 9. The method of claim 1, wherein the compound is (−)-6-chloro-4-E-cyclopropylethenyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
 10. The method of claim 3, wherein the compound is (−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
 11. The method of claim 3, wherein the compound is (+)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
 12. The method of claim 3, wherein the compound is (+)-4-cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, or a pharmaceutically acceptable salt is form thereof.
 13. The method of claim 3, wherein the compound is (−)-4-cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
 14. The method of claim 3, wherein the compound is (+)-E-4-cyclopropylethenyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
 15. The method of claim 3, wherein the compound is (−)-6-chloro-4-E-cyclopropylethenyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
 16. The method of claim 2, wherein the compound is (+)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
 17. The method of claim 2, wherein the compound is (+)-4-cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
 18. The method of claim 2, wherein the compound is (−)-4-cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
 19. The method of claim 2, wherein the compound is (+)-E-4-cyclopropylethenyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
 20. The method of claim 2, wherein the compound is (−)-6-chloro-4-E-cyclopropylethenyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, or a pharmaceutically acceptable salt form thereof. 